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Macrovascular Residual Risk Studies

1 July 2009
The Heart Protection Study: statin therapy significantly decreased vascular risk in high-risk diabetic patients but 78% of major vascular events were not prevented
MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.
Heart Protection Study Collaborative Group.
Objective: To assess the effects on vascular mortality and morbidity of a substantial LDL-cholesterol (LDL-C) reduction maintained for several years in a large cohort cohort of high-risk diabetic individuals (90% with type 2 diabetes).
Inclusion criteria: Non-fasting blood total cholesterol concentrations ≥ 3.5 mmol/L (135 mg/dL) and a medical history of coronary disease, occlusive disease of non-coronary arteries, or treated hypertension.
Exclusion criteria: Statin therapy clearly indicated or contraindicated; myocardial infarction, stroke or hospital admission for angina within the previous 6 months; concurrent treatment with cyclosporin, fibrates, or high-dose niacin.
Study population: 5963 UK diabetic patients aged 40-80 years (90% with type 2 diabetes)
Intervention: Patients randomly allocated to receive 40 mg simvastatin daily or matching placebo.
Primary endpoint: First major coronary events (non-fatal myocardial infarction or death from coronary disease) and first major vascular events (major coronary events, strokes, and coronary or non-coronary revascularizations)
Secondary endpoint: Time to first occurrence of individual components of the primary composite endpoint; all-cause mortality.
Study design: Randomized, double-blind, parallel group study of primary and secondary prevention
(≈50% with history of vascular disease)
Method: Log rank test, ITT analysis, mean follow-up 4.8 years.
Main results: 22% (95% Cl 13-30) reduction in first occurrence of major coronary events, strokes, and revascularizations (p<0.0001)
Author's conclusion: Statin therapy should be considered routinely in all diabetic patients at sufficiently high risk for macroangiopathy
Figure 1. Relative risk reduction and residual risk of first major vascular event in patients treated with simvastatin 40 mg/day compared with placebo in different subgroups. Note that the highest levels of residual risk are seen in patients with both diabetes and components of atherogenic dyslipidemia
(low HDL-C and elevated TG levels).


The MRC/BHF Heart Protection Study was the first randomized double-blind, placebo-controlled clinical trial evaluating the effects of LDL-C lowering therapy in a representative sample of patients with (mostly type 2) diabetes. This somewhat complex design also included high-risk non-diabetic patients, although the present comment refers exclusively to the HPS diabetic population.

HPS was conducted in diabetic patients at particularly high risk of major vascular events
The study inclusion criteria selected patients at very high risk for cardiovascular disease, even though their LDL-C was not particularly elevated at baseline (mean: 3.2 ± 0.82 mmol/L; 125 ± 32 mg/dL). Together with diabetes, a powerful cardiovascular risk factor in itself, 19% of the 5963 participants had a history of prior myocardial infarction, 32% had another occlusive arterial disease and 68% were current or ex-smokers. Although hypertensive patients had to be on treatment to be included, mean blood pressure was 148/82 mm Hg, a level well-above the target of 130/80 mm Hg currently recommended for diabetic patients.

A confounding effect in this study was that participants and their attending physicians were informed of beneficial results of newly-completed statin trials and encouraged to use a non-study statin if they considered that it was indicated. This resulted in a 17% “drop-in” effect in the placebo group. In the active treatment group, 82% of patients were compliant with their allocated simvastatin monotherapy, 3% received a non-study statin as monotherapy alone, and 2% both simvastatin and a non-study statin.

After a mean 5-year follow-up, treatment with simvastatin 40 mg daily was associated with a mean decrease in LDL-C level of 1.0 mmol/L (39 mg/dL) compared with placebo.

The relative risk of major vascular events was significantly reduced by 22% (p<0.0001). As the effect did not differ in patients with LDL-C levels less than or greater than 3.0 mmol/L (116 mg/dL), the authors recommended routine use of statin for all diabetic patients at sufficiently high risk of major vascular events, irrespective of pre-statin LDL-C levels. Subgroup analyses showed no significant differences according to gender, age, diabetes duration, or HbA1c <7.0 vs. ≥7.0%.

Simvastatin alone leaves a high residual risk of macrovascular events in diabetes patients
The global results of HPS would indicate that treatment with simvastatin 40 mg daily prevents 22% of major macrovascular events in diabetic patients. These data were confirmed by a subsequent meta-analysis of 14 statin trials including 18,686 diabetic patients, which showed a 21% reduction in relative risk of major vascular events per 1.0 mmol/L reduction in LDL-C (p<0.0001) during a mean follow-up of 4.3 years.1

Despite statin therapy, however, a high residual macrovascular risk – 78% – remained. The HPS data suggested wide variation in the efficacy of simvastatin monotherapy, which was dependent on baseline risk level rather than LDL-C levels at baseline. For example, secondary prevention diabetes patients benefited much less from simvastatin therapy than primary prevention diabetes (risk reduction was only 11.5%). These findings implicated other factors beyond LDL-C in residual macrovascular risk in high-risk patients with diabetes.

Thus, while the HPS results have had a major impact on the management of patients with diabetes, these findings also underline the need to envisage newer therapeutic strategies to reduce the extensive macrovascular residual risk persisting in statin-treated high-risk diabetic patients.

Beyond LDL-C: atherogenic dyslipidemia, an major component of lipid-related macrovascular residual risk 
The lipid profile of the HPS participants was also characterized by abnormal non-LDL-C lipids. While LDL-C levels were modestly elevated (although lower than levels observed in non-diabetic patients), HDL-C levels were low (1.06 ± 0.36 mmol/L or 41 ± 14 mg/dL) and triglyceride levels were markedly elevated (2.3 ± 1.59 mmol/L or 205 ± 141 mg/dL). This combination of low HDL-C and elevated triglycerides, atherogenic dyslipidemia, is typically observed in type 2 diabetes patients, whose lipoprotein profile often shows relative enrichment in small, dense LDL particles, which promote lesser LDL-C levels relative to LDL number.

Simvastatin 40 mg had only modest effects on atherogenic dyslipidemia, raising HDL-C by <1% (0.01 ± 0.01 mmol/L or 0.39 ± 0.39 mg/dL) and reducing triglycerides by 13% (0.3 ± 0.06 mmol/L or 26.7 ± 5.3 mg/dL). Subgroup analyses also showed that the relative reduction in cardiovascular risk was lower in patients with either elevated triglycerides (12.8%) and/or low HDL-C (16.6%), leaving this subgroup with a higher residual vascular risk load (Figure 1). These data underline the potential benefit to consider additional lipid-modifying therapy targeting non-LDL lipids in high-risk type 2 diabetes patients.

A logical approach to reduce the non-LDL-related modifiable component of macrovascular residual risk observed in the HPS (and other statin trials) would be to combine a statin with a drug with established efficacy to impact non-LDL-C confirmed in landmark lipid-lowering monotherapy trials, such as niacin or a fibrate. Such a lipid-lowering bitherapy strategy is currently evaluated in major prospective trials with hard cardiovascular endpoints, such as the recently published ACCORD Lipid (fenofibrate-statin) and the ongoing AIM-HIGH (niacin-statin) trials.


References 1.Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008 Jan 12;371:117-25 
Key words Type 2 Diabetes – Macrovascular Residual Risk – Statin therapy