Triglycerides in risk prediction in primary prevention

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10 January 2018

According to this analysis based on the Copenhagen studies, current European guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) need to be updated to take into account elevated triglycerides in risk prediction.

Madsen CM, Varbo A, Nordestgaard BG. Unmet need for primary prevention in individuals with hypertriglyceridaemia not eligible for statin therapy according to European Society of Cardiology/European Atherosclerosis Society guidelines: a contemporary population-based study. Eur Heart J 2017; doi:10.1093/eurheartj/ehx659.

STUDY SUMMARY

Objective:

To identify individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), who are not eligible for statin treatment according to the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines, based on high plasma triglycerides.

Study design:

Population based study

Study population:

Data from 58 547 individuals from the Copenhagen General Population Study aged 40–65 years and free of ASCVD, diabetes, and statin use at baseline were included.

Primary variable:

· Eligibility for statin treatment, based on the European SCORE risk tables and 2016 ESC/EAS guidelines.

· Cardiovascular endpoints were myocardial infarction (MI), and major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal MI, unstable angina pectoris, and stroke.

· Absolute risk, defined as incidence rates for MACE per 1000 person-years, and estimated 10-year risk (%).

Methods:

Absolute 10-year risks of MI and MACE were estimated nonparametrically. Cumulative incidence curves were estimated with death (excluding cardiovascular deaths for the MACE endpoint) and emigration as competing events, and age as the underlying timescale.

Subhazard ratios and corresponding P-values were obtained using competing risk regression.

Individuals who were not eligible for statins were subdivided into six groups based on their triglyceride concentrations with 1 mmol/L (88mg/dL) cutpoints, as well as into two larger groups (triglycerides < or ≥3.0 mmol/L [264mg/dL]).

Results:

Of patients ineligible for statin treatment based on ESC/EAS guidelines, 79% had triglycerides <3.0 mmol/L and a further 7% had triglycerides ≥3.0 mmol/L.

Over the median follow-up of 8 years (range 0–13 years), 1,770 subjects experienced a MACE and 734 an MI, giving overall incidence rates per 1000 person-years of 3.9 [95% confidence interval (95% CI) 3.7–4.1] for MACE and 1.6 (1.5–1.7) for MI. High concentrations of triglycerides were associated with high absolute risk of ASCVD in individuals who were not eligible for statin treatment according to the 2016 ESC/EAS guidelines; notably, 7% of individuals with triglycerides ≥3.0 mmol/L were at high risk of ASCVD (see Table).

Table. Cumulative incidence and 10-year risk of events, according to statin eligibility and triglycerides

Outcome/incidence or risk	Statin ineligible TG <3.0 mmol/L	Statin ineligible TG ≥3.0 mmol/L	Statin eligible
MACE
Cumulative incidence, % (95% CI)	8.1 (7.3–8.9)	14.6 (12.6–16.8)	16.5 (14.0–19.3)
10-year risk, % (95% CI)	2.8 (2.6–3.0)	5.7 (4.9–6.6)	7.6 (6.9–8.3)

MI
Cumulative incidence, % (95% CI)	3.0 (2.7–3.3)	7.8 (6.4–9.5)	7.1 (5.9–8.4)
10-year risk, % (95% CI)	1.0 (0.9–1.1),	3.0 (2.4–3.7),	3.3 (2.8–3.7)

Authors’ conclusion:

High concentrations of triglycerides identify individuals at high risk of ASCVD amongst those not definitely eligible for statin treatment according to the 2016 ESC/EAS guidelines. This points towards an unmet need for primary prevention, calling for expansion of guidelines on statin eligibility and the need for future placebo-controlled randomized controlled trials in individuals with hypertriglyceridaemia.

COMMENT

Elevated triglycerides – a marker of levels of triglyceride-rich lipoproteins and their remnants - as a causal factor in ASCVD has gained renewed focus, with accumulating evidence from observational and genetic studies (1,2). Now, this analysis from the Copenhagen General Population Study has defined the part of plasma triglycerides in cardiovascular risk prediction. Despite being ineligible for statin therapy on the basis of current European guidelines, individuals with triglycerides ≥3.0 mmol/L were at high risk of ASCVD events, with a 10-year risk for MACE of 5.7% (compared with 7.6% for statin eligible subjects). Moreover, according to data from the Copenhagen General Population Study, 7% - or 1 in 14 primary prevention subjects – would fit in this category.

These findings imply that elevated triglycerides should be taken into account in global risk prediction scores used in current guidelines. One reason that this has not been done is the lack of definitive evidence from randomized controlled trials in subjects with high triglycerides. The authors highlight the need for such studies to address this unmet clinical need. Three phase III trials are currently ongoing in subjects on background statin therapy; two with n-3 fatty acids therapy (REDUCE-IT, ClinicalTrials number NCT01492361 and STRENGTH; NCT02104817) and one with the selective peroxisome proliferator activator receptor-alpha modulator pemafibrate (PROMINENT; NCT03071692). These critical studies will provide important information of relevance to clinical guidelines.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.

2. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63.

· A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT) https://clinicaltrials.gov/ct2/show/NCT01492361

· Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) https://clinicaltrials.gov/ct2/show/NCT02104817

· Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) (PROMINENT) https://clinicaltrials.gov/ct2/show/NCT03071692

Key words

triglycerides; global risk prediction; Copenhagen General Population Study; guidelines; pemafibrate; PROMINENT