Elsevier

The Lancet

Volume 361, Issue 9374, 14 June 2003, Pages 2005-2016
The Lancet

Fast track — Articles
MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(03)13636-7Get rights and content

Summary

Background

Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk.

Methods

5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14 573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1·0 mmol/L (39 mg/dL) during the 5-year treatment period.

Findings

Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for re-vascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% Cl 13-30) reduction in the event rate (601 [20·2%] simvastatin-allocated vs 748 [25·1%] placebo-allocated, p<0·0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% Cl 17–46, p=0·0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% Cl 13–40, p=0·0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3-0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5-0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period.

Interpretation

The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.

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.

Section snippets

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

References (46)

  • DR Arday et al.

    Variation in diabetes care among states: do patient characteristics matter?

    Diabetes Care

    (2002)
  • National Service Framework for diabetes: standards

  • Standards of medical care for patients with diabetes mellitus

    Diabetes Care

    (2002)
  • D Jacobs et al.

    Report of the conference on low blood cholesterol: mortality associations

    Circulation

    (1992)
  • J Stamler et al.

    Diabetes, other risk factors and 12–year cardiovascular mortality for men screened in the multiple risk factor intervention trial

    Diabetes Care

    (1993)
  • J Chen et al.

    Diet, life–style and mortality in China

    (1990)
  • Z Chen et al.

    Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations

    BMJ

    (1991)
  • RC Turner et al.

    Risk factors for coronary artery disease in non–insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23)

    BMJ

    (1998)
  • Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

    Lancet

    (1994)
  • FM Sacks et al.

    The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels

    N Engl J Med

    (1996)
  • The effect of aggressive lowering of low–density lipoprotein cholesterol levels and low–dose anticoagulation on obstructive changes in saphenous-vein coronary–artery bypass grafts

    N Engl J Med

    (1997)
  • Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

    N Engl J Med

    (1998)
  • K Pyorala et al.

    Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease

    Diabetes Care

    (1997)
  • Cited by (2674)

    • Contemporary Treatment of the Asymptomatic Carotid Patient

      2023, Surgical Clinics of North America
    • Statins and diabetes: What are the connections?

      2023, Best Practice and Research: Clinical Endocrinology and Metabolism
    View all citing articles on Scopus

    Collaborators and participating hospitals are listed on The Lancet website (http://image.thelancet.com/extras/03art3418webappendix.pdf)

    View full text