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Macrovascular Residual Risk Studies

13 May 2014
Importance of targeting obesity to reduce residual cardiovascular risk
This pooled analysis including 1.8 million subjects from 97 studies reinforces the importance of obesity as a contributor to residual cardiovascular risk beyond treatment of high blood pressure, cholesterol and glucose.
Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects). Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million participants. Lancet 2014; 383: 970-83.
Objective: To investigate the effects of body mass index (BMI) on risk for coronary heart disease (CHD) and stroke mediated through blood pressure, cholesterol, and glucose, and whether these effects are independent of these factors.
Study design: Pooled analysis of data from 97 prospective cohort studies (1948-2005), including 1.8 million subjects with 57,161 CHD and 31,093 stroke events. All studies had at least one year of follow-up. .
Study population:

Subjects included in the analysis were ≥18 years, had a BMI of ≥20 kg/m², and no prior history of CHD or stroke.

Primary variable:

• CHD, defined as fatal or non-fatal ischaemic heart disease, including acute myocardial infarction and angina pectoris
• Stroke, defined as fatal or non-fatal cerebral infarction, and intracerebral or subarachnoid haemorrhage.


BMI was the main measure of adiposity, and was analysed as a continuous variable. The variables for mediators included systolic blood pressure or hypertension status for blood pressure; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol concentrations, or hypercholesterolaemia for serum cholesterol; and fasting and postprandial glucose, haemoglobin A1c, or diabetes status for blood glucose. The hazard ratio (HR) of BMI on risk for CHD or stroke with and without adjustment for all possible combinations of the 3 mediators blood pressure, cholesterol, and glucose was calculated. Pooled HRs were calculated using a Cox proportional hazards regression random-effects model with inverse variance weights.

The study first analysed the effect of 5 kg/m² higher baseline BMI on CHD and or stroke with adjustment for confounders. Mediators were then added to the model, separately, in all combinations of two, and all three together. In addition, categories of overweight (BMI ≥25–<30 kg/m²) and obesity (BMI ≥30 kg/m²) versus normal weight (BMI ≥20–<25 kg/m²) were analysed using the same methods.


Key findings are summarised in Table 1.
Blood pressure, blood glucose and cholesterol accounted for 31%, 15% and 10% of the excess risk for CHD. The excess risk mediated by all 3 mediators did not differ significantly between Asian and Western subjects.

Table 1. Hazard ratio (95% confidence interval) for each 5 kg/m2 increase in BMI

Adjusted for




1.27 (1.23 to 1.31)

1.18 (1.14 to 1.22)

All 3 mediators

1.15 (1.12 to 1.18)

1.04 (1.01 to 1.08)

Excess risk due to BMI

46% (95% 42 to 50)

76% (65 to 91)

Compared with normal weight, being overweight or obese was associated with 50% (44–58%) and 44% (41–48%), respectively, excess risk of CHD, and 98% (69–155%) and 69% (64–77%), respectively, excess risk of stroke mediated by blood pressure, blood glucose and cholesterol.

Authors’ conclusion: Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of the excess risk of CHD and three-quarters of the excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.


Increased BMI is a well-recognised cardiovascular risk factor.(1) Adiposity can increase blood pressure and predispose to dyslipidaemia, inflammation and the development of insulin resistance and type 2 diabetes. Not surprisingly, the world-wide escalation in obesity rates has led to justifiable concerns about the corresponding impact on prevalence of cardiometabolic disease. Indeed, a particular cause for concern is the Latin America region, where obesity and related cardiometabolic disease are now the most important public health concern; by 2040, Brazil is anticipated to ‘top the global league’ for cardiovascular mortality.(2)

Furthermore, increased BMI counters the established benefits of effective strategies targeting high blood pressure, cholesterol and blood glucose. In this study, being overweight was associated with 50% excess risk of CHD and 98% excess risk of stroke compared with individuals with normal weight with targeted treatment of these three mediators of risk. This finding clearly argues for sustained intervention at the public health levels to address the burden of obesity and thus optimise the benefits of these therapeutic strategies.

A second key finding highlights the magnitude of benefits that accrue from successful therapeutic intervention targeting high blood pressure, hypercholesterolaemia and hyperglycaemia even among individuals who are overweight or obese, reducing the excess risk of CHD by ∼50% and of stroke by ∼75%. These findings may provide further support for a ‘polypill’ of established inexpensive treatments targeting all three mediators to optimise adherence and thus potential benefit, particularly in lower-income regions with limited healthcare budgets.(3,4) However, it is also evident that the association between adiposity and cardiovascular disease is not completely explained by these three mediators. Even with optimal management of blood pressure, blood glucose and cholesterol, a substantial residual cardiovascular risk persists. This residual risk undoubtedly relates to both recognised and emerging risk factors, as highlighted in the most recent definition proposed by the Residual Risk Reduction Initiative (R3i). In this definition, residual vascular risk, i.e. of micro- and macro-vascular events, encompasses both the risk from established risk factors (such as unhealthy lifestyles, dyslipidaemia, high blood pressure, high blood sugar and obesity) and emerging risk factors that persist despite current evidence-based medical care. Consequently, these data not only provide a strong rationale for optimising the management of recognised modifiable risk factors, but also highlight the need for research aimed at identifying other potential contributors, including those mediated by inflammatory and thrombogenic pathways. Both components are consistent with the mission of the R3i.

This analysis has a number of important strengths. First, it represents the largest pooled analysis of multiple cardiovascular disease risk factors, including data from 1.8 million subjects. Second, the analysis included both Western and Asian cohorts, which enabled analysis of the impact of BMI in different ethnicities. The fact that the study showed consistent findings irrespective of the ethnicity of the cohort provides a clear rationale for sustained approaches targeting weight reduction and potential treatment gaps in the implementation of guideline-recommended therapeutic strategies. To ensure the long-term success of such approaches clearly requires vested commitment at the public policy level.


1. Whitlock G, Lewington S, Sherliker P et al, and the Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373: 1083–96.
2. Leeder S et al. A race against time: The challenge of cardiovascular disease in developing economies. Earth Institute at Columbia University. Available at:
3. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-23
4. Thom S, Poulter N, Field J et al; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918-29.

Key words

obesity; residual risk; coronary heart disease; stroke; cholesterol; blood pressure; blood glucose