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Macrovascular Residual Risk Studies

28 February 2017
STRONG HEART study: relationship between atherogenic dyslipidaemia and risk of cardiovascular disease depends on diabetes status.
This longitudinal prospective study in American Indians showed that the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), in the context of diabetes status, identifies subgroups of patients at increased cardiovascular risk.
Lee JS, Chang P-Y, Zhang Y et al. Triglyceride and HDL-C dyslipidemia and risks of coronary heart disease and ischemic stroke by glycemic dysregulation status: The Strong Heart Study. Diabetes Care 2017; DOI: 10.2337/dc16-1958 [Epub ahead of print]
Objective: To investigate whether the relationship between elevated triglycerides and low HDL-C (atherogenic dyslipidaemia) and cardiovascular risk depends on glycaemic dysregulation, sex, or low-density lipoprotein cholesterol (LDL-C) levels.
Study design: Community-based, prospective cohort study of American Indians who were enrolled between 1989 and 1991 (median follow-up 17.7 years).
Study population: 3,216 individuals (mean age 56 years, 40% men, 41% with diabetes) who were free of cardiovascular disease (CVD) at baseline.
Efficacity measures: Primary endpoint: incident cardiovascular events, defined as fatal or nonfatal ischaemic stroke and coronary heart disease (CHD), identified by annual morbidity and mortality surveillance.

Secondary endpoints: Lipid parameters
Fasting triglycerides, categorized as normal (<150 mg/dL) or high (≥150 mg/dL)
Fasting HDL-C levels, categorized as normal (≥40 mg/dL for men and ≥50 mg/dL for women) or low (<40 mg/dL for men and <50 mg/dL for women)
Methods: Triglycerides-HDL-C status was categorized using the above criteria.  Cox proportional models controlling for age, sex, body mass index, smoking, diabetes, fasting LDL-C level, use of antihypertensive medications, physical activity, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident ischaemic stroke and CHD in relation to combined triglycerides and HDL-C status. A p-value for interaction of 0.05 was considered statistically significant for effect modification.?
Main results:
  • At baseline, triglycerides-HDL-C status was normal in 37% of individuals; 30% had low HDL-C only, 9% had elevated triglycerides only, and 24% had both high triglycerides and low HDL-C. Diabetes was present in 60% of subjects with high triglycerides-low HDL-C but only 30% with normal values for both lipid measures.


  • During a median follow-up time of 17.7 years (interquartile range 15.2 to 18.6 years), 789 individuals had a CHD event (202 with fatal events) and 158 had an ischaemic stroke (11 with fatal events). Overall, the incidence rates of CHD and ischaemic stroke were 18.6 (95% CI 17.6–19.3) and 3.7 (95% CI 3.1–4.3) per 1,000 person years, respectively.


  • Individuals with high triglycerides and low HDL-C had a 1.32-fold greater risk (95% CI 1.06–1.64) for CHD, and 1.46-fold (95% CI 0.92–2.33) greater risk for ischaemic stroke. In individuals with diabetes, this risk was significantly higher than in those without diabetes (Table).


Table. Impact of high triglycerides-low HDL-C dyslipidaemia on risk for cardiovascular events, fully adjusted model


No diabetes (n=1,882)

Diabetes (n=1,334)


Incidence; n (%)

HR (95% CI)

Incidence; n (%)

HR (95% CI)


50 (17%)

0.88                     (0.60–1.29)

192 (43%)

1.54                   (1.15–2.06)

Ischaemic stroke

17 (6%)

1.16                     (0.55–2.45)

40 (9%)

2.13                     (1.06–4.29)

Hazard ratio versus reference, i.e. normal triglycerides and normal HDL-C levels

Authors’ conclusion: American Indian adults with both high triglycerides and low HDL-C, particularly those with diabetes, have increased risks of incident CHD and stroke.


Consistent with this month’s theme, this report from the Strong Heart Study provides evidence that the combination of elevated fasting triglycerides and low HDL-C, atherogenic dyslipidaemia, is associated with increased cardiovascular risk in American Indians, especially in those with diabetes. Thus, the study adds evidence that reaffirms the link between atherogenic dyslipidaemia and cardiometabolic risk across the range of ethnic groups.1

These findings are important in the context of the characteristics of this cohort. American Indians are known to have disproportionately high rates of obesity and diabetes, when compared with European populations.2 While a previous report highlighted elevated LDL-C as a risk factor for CHD in this cohort,3 the current report emphasises the importance of lipid factors beyond LDL, notably atherogenic dyslipidaemia, as contributors to this risk.  Moreover, the study shows that it is the dysregulation of glycaemia (and/or the underlying factors leading to hyperglycaemia), rather than other causes, that drive this risk in individuals with atherogenic dyslipidaemia.

Taken together, these findings highlight the importance of recognizing atherogenic dyslipidaemia in insulin resistant and/or hyperinsulinaemic patient groups and targeting this dyslipidaemia with appropriate therapeutic strategies. Fibrates may represent one option currently available, as shown by a meta-analysis of the major fibrate trials,4 although given the limited potency of these agents due to dose-related adverse effects, novel approaches are also needed.

References 1. McQueen MJ, Hawken S, Wang X et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet 2008;372:224-33.
2. Zhao Q, Zhu Y, Best LG et al. Metabolic profiles of obesity in American Indians: The Strong Heart Family Study. PLoS One. 2016 Jul 19;11(7):e0159548.
3. Xu J, Lee ET, Peterson LE et al. Differences in risk factors for coronary heart disease among diabetic and nondiabetic individuals from a population with high rates of diabetes: the Strong Heart Study. J Clin Endocrinol Metab 2012 ;97:3766-74.
4. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692–5.
Key words residual cardiovascular risk; diabetes; atherogenic dyslipidaemia; Strong Heart Study