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R3i EDITORIAL

22 August 2016

Atherogenic dyslipidaemia: a risk factor for silent coronary artery disease

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Clinical trials aim to assess the impact of treatments on risk for cardiovascular events, hard clinical endpoints which can be readily and objectively evaluated. However, this month’s Focus article 1 raises the issue of asymptomatic coronary artery disease (CAD), especially in high risk patients such as those with type 2 diabetes, and how best to direct efforts to reduce the high residual risk of silent CAD.

Silent CAD is more common than previously thought. While estimates vary, depending on the population studied and assessment procedures, it is thought that 15-35% of high risk individuals may be affected (2-4). In newly diagnosed type 2 diabetes patients, the UK Prospective Diabetes Study reported that about one in 6 individuals had ECG evidence of silent myocardial infarction (SMI), and this was independently associated with an increased risk of fatal myocardial infarction and all-cause mortality 2. This prevalence was higher with increased age, as well as increased duration of diabetes 3,4. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, silent MI accounted for nearly 40% of first cases of MI; after first MI, about two-thirds of cases were SMI 5. The poor prognosis of SMI highlights the need for early detection and appropriate therapeutic approaches to reduce the high residual risk of this condition despite best evidence-based treatment.

Atherogenic dyslipidaemia: a contributor to silent CAD

Against this background, this month’s Focus brings important new information, showing that atherogenic dyslipidaemia, the combination of elevated triglycerides and low high-density lipoprotein cholesterol, is an important contributor to the risk of silent myocardial ischaemia and asymptomatic CAD. The authors evaluated 1,080 asymptomatic patients with type 2 diabetes and a normal resting ECG, who had at least one additional risk factor and low-density lipoprotein cholesterol (LDL C) levels <3.35 mmol/L (130 mg/dL). Given that this patient population was characterised by longstanding diabetes (mean 13.8 years), and a high prevalence of cardiovascular risk factors (76% had hypertension, 57% had nephropathy, 23% smoked and 13% had a family history of premature CAD), it is perhaps surprising that only 41% were on a statin. Silent myocardial ischaemia was identified by stress testing in 27% of patients and CAD subsequently confirmed in 42% of these patients, in line with previous reports of prevalence.

In this cohort, 60 patients had evidence of atherogenic dyslipidaemia (defined in this study by the combination of fasting triglycerides ?2.26 mmol/L (200 mg/dL) and high-density lipoprotein cholesterol ?0.88 mol/L (34 mg/dL) for both genders). This dyslipidaemic profile was shown to be independently associated with an increased risk of silent myocardial ischaemia (odds ratio 1.8, 95 % confidence interval 1.0–3.3, p < 0.05), as well as 4-fold increased risk of silent CAD (odds ratio 4.0, 95% confidence interval 1.7–9.2, p < 0.001). This increased risk of silent CAD persisted in patients with well controlled LDL-C levels (<2.6 mmol/L or <100 mg/dL). Although corroboration is required in other studies, these findings are strengthened by firstly, the size of the cohort and secondly, the fact that the prevalence of SMI reported was in line with that previously reported 3.

How best to reduce this risk?

There is clear evidence from a meta-analysis of fibrate trials, albeit post hoc, that targeting atherogenic dyslipidaemia reduces cardiovascular events in high risk individuals 6. Moreover, subgroup analysis from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that targeting this dyslipidaemia in statin-treated type 2 diabetes patients managed according to best standards of care, reduced the residual risk of cardiovascular events by 30% (versus 8% in all patients) 7. Data from the FIELD study also showed that treatment with fenofibrate reduced the risk of subsequent cardiovascular events by 78% in type 2 diabetes patients with SMI 8.

As proposed by the authors, management should have two key aims: screening for silent CAD and best evidence-based therapeutic approaches. Detecting the presence of atherogenic dyslipidaemia can not only help to identify silent CAD earlier, but also help in targeting therapy to reducing this dyslipidaemic profile. And, following on from last month’s editorial, the key question is whether novel therapies with potential for improved efficacy against atherogenic dyslipidaemia, may help to further reduce the high residual risk of both symptomatic and asymptomatic CAD in these high risk patients.

References

1. Valensi P, Avignon A, Sultan A. Atherogenic dyslipidemia and risk of silent coronary artery disease in asymptomatic patients with type 2 diabetes: a cross?sectional study. Cardiovasc Diabetol 2016;15:104 .
2. Davis TM, Coleman RL, Holman RR; UKPDS Group. Prognostic significance of silent myocardial infarction in newly diagnosed type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79. Circulation 2013;127:980-7.
3. Valensi P, Lorgis L, Cottin Y. Prevalence, incidence, predictive factors and prognosis of silent myocardial infarction: A review of the literature. Arch Cardiovasc Dis 2011;104:178—88.
4. Arenja N, Mueller C, Ehl NF et al. Prevalence, extent, and independent predictors of silent myocardial infarction. Am J Med 2013;126:515-22.
5. Burgess DC, Hunt D, Li L et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Eur Heart J 2010;31:92—9.
6. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
7. The ACCORD study group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.
8. Burgess DC, Hunt D, Li L et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Eur Heart J 2010;31:92–9.