Elevated ‘Lipid-Years’ in Young Adulthood Tied to Later Cardiovascular Disease

The concept of LIFETIME cardiovascular disease (CVD) risk is beautifully demonstrated in the study published online January 26, 2015 in Circulation [1].

Fifty-five-year-olds who had prolonged moderately elevated non–HDL (total atherogenic lipoproteins) levels (>160 mg/dL/ 4.0 mmol/L) when they were young adults were much more likely than their peers to have coronary heart disease by the time they were 70. In an analysis based on the Framingham Offspring Cohort the risk of cardiovascular disease (defined as myocardial infarction, angina, coronary insufficiency, or death from CVD) increased with exposure to elevated non-HDL levels in a dose-dependent way.

Specifically, during follow-up, 16.5% of the middle-aged adults who had abnormal atherogenic lipoproteins in the past 11 to 20 years developed CVD, but only 8.1% of those with elevated non-HDL in the past 1 to 10 years developed CVD. In contrast among the adults without elevation of non-HDL, only 4.4% developed CVD.

Atherogenic LP

Having decades of exposure to what many would consider to be mild to moderately elevated atherogenic lipoproteins is associated with a significantly elevated risk of cardiovascular disease. Thus, the way we think about smoking in terms of pack-years, we should be thinking about ‘atherogenic lipid-years’ [of exposure to high non-HDL].

For young adults, we really need to remember that the foundation for cardiovascular disease is being laid in our 20s, 30s, and 40s, so aggressive risk-factor modification at that age is really important. For middle-aged adults, “in the same way that a 55-year-old with a family history of cardiovascular disease [or] an increased coronary calcium score would be considered higher risk, we should take into consideration the duration of exposure to high non-HDL . . . to stratify risk.”

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Decades of High Atherogenic Lipoproteins: A New CVD Risk Factor?

Atherosclerosis develops slowly over many years starting in childhood, and the effects of prolonged exposure to elevated atherogenic lipoproteins in young adulthood have previously not been well-defined. This research group examined data from 1478 individuals in the offspring cohort of the Framingham Heart Study who were approximately 55 years old and did not have a history of CVD when they were enrolled during 1987 to 1998.

Participants were stratified into three groups based on hyperlipidaemia (non–HDL >160 mg/dL/ 4.0 mmol/L) at enrolment. A total of 512 participants had no hyperlipidaemia; 389 participants had 1 to 10 years of hyperlipidaemia; and 577 had 11 to 20 years of hyperlipidaemia.

Only 85 participants (5.8%) were on lipid-lowering treatment at baseline.

During a median follow-up of 15 years, there were 136 cardiac events. The unadjusted risk of CVD doubled for every 10 years of exposure to hyperlipidaemia during age 35 to 55 (HR 2.0, 95% CI 1.63–2.45 per decade of hyperlipidaemia).

The association was attenuated but remained statistically significant after adjustment for sex, age, systolic blood pressure, antihypertensive therapy, smoking status, HDL, diabetes, and non–HDL cholesterol at baseline (adjusted HR 1.39, 95% CI 1.05–1.85 per decade of hyperlipidaemia). The association also remained significant after adjustment for lipid-lowering–therapy use at baseline and follow-up.

10 yr and lifetime risk

Based on the 2013 ACC/AHA Cholesterol Guidelines (using the 10-year CVD risk threshold of >7.5%), among the 55-year-old adults who had been exposed to high non-HDL for 11 to 20 years, 15.1% would have met the criteria for statin therapy at age 40 and 34.8% would have met criteria at age 50. However, this study was not designed to determine whether early statin intervention in young adults “on the hyperlipidaemia trajectory” would decrease future CVD risk.

However, it’s certainly not a stretch to say that at least adults in their 50s who have had long-term exposure to high atherogenic non-HDL (total ApoB) should be considered for statin therapy, and there are [randomized clinical trial] data to support the efficacy in that group.

This study used non–HDL cut-offs, since HDL was measured directly whereas LDL was calculated. Typically, non–HDL is 30 mg/dL/ 0.75 mmol/L higher than LDL, and the researchers found similar results using a LDL level of >130 mg/dL/ 3.2 mmol/L.

Individuals who had average non–HDL levels during the preceding 20 years that were below 125 mg/dL/ 3.1 mmol/L had a similar low risk of CVD, and those with levels above 195 mg/dL/ 4.8 mmol/L had a similar high risk of CVD. For every 10-point increase in non–HDL between 125 and 195 mg/dL, there was a 33% increased risk of CVD.

This begs the question as to what constitutes the normal range of non-HDL but in my hands I aim to keep atherogenic lipoproteins (non-HDL or total Apo B) less than 120 mg/dL/ 3.0 mmol/L or 0.8 for Apo B.

Nevertheless, this study identifies adults who may benefit from more aggressive primary prevention and again flies in the face of those sceptics who treat (atherogenic) lipoproteins with no respect.

7 things to reverse CVDThese findings suggest that adults with longstanding moderate elevations in non–HDL levels should be added to those already identified by the current guidelines as candidates for an informed patient-physician discussion about appropriate lipid-management strategies to reduce future risk of heart disease.

References

  1. Navar-Boggan A, Peterson E, D’Agostino R, et al. Hyperlipidaemia in young adulthood increases long-term risk of coronary heart disease. Circulation 2015

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Women Benefit from Statin Therapy

Billed as the most comprehensive of its kind, a large meta-analysis (all of the large statin trials are represented in this analysis) suggests that statin benefits in reducing “major vascular events” are about the same in women as in men when adjusted for predicted cardiovascular risk [1].

dt_150113_equality_for_women_800x600

Bearing in mind that approximately 20 million will die worldwide this year from cardiovascular disease, with 55% of the epidemic expressed in women. It’s therefore unfortunate that the idea has grown up in some places that women don’t benefit as much as men from statin therapy, and I think this idea has arisen because people haven’t taken into account the fact that women in general develop vascular disease later in life than men.

It is critical to identify women who are at risk for cardiovascular disease and offer them statin therapy if they exceed a certain threshold of risk, because vascular disease is common, especially in older women, and prevention of that disease could be facilitated by wider use of statin therapy.

heart-disease-woman

The study was published online on January 9, 2015 in the Lancet.

The Cholesterol Treatment Trialists’ (CTT) Collaboration performed meta-analyses on data from 22 trials of statin therapy vs controls and five trials of more intensive vs less intensive statin therapy. A total of 46 675, or 27% of 174 149 randomly assigned participants in these trials, were women. Individual participant data were available from all 27 trials.

In each group of trials, mean concentrations of total and LDL cholesterol at baseline were similar in women as they were in men.

All trials (n=27)

Group Total cholesterol, mmol/L LDL cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L
Women 5.6 3.4 1.3 1.5
Men 5.3 3.3 1.1 1.6

Major Vascular Events

Among all 27 trials, statins reduced the risk of major vascular events by 21% for each 1.0-mmol/L reduction in LDL cholesterol (rate ratio 0.79, 95% CI 0.77–0.81; P<0.0001), with significant reductions in both women and women.

Major vascular events included MI, stroke, the need for coronary revascularization, and cardiac death.

The proportional reductions in major vascular events for each 1.0-mmol/L reduction in LDL cholesterol seemed slightly smaller in women than in men among the 22 trials of statin vs controls, but they were still highly significant (P<0.0001) in both women, at a rate ratio (RR) of 0.85 (99% CI 0.78–0.92), and men (RR 0.78, 95% CI 0.75–0.82).

Among the five trials where more intensive therapy was compared with less intensive therapy, the proportional reductions in major vascular events among women were similar to those in men. The proportional reductions in major vascular events were also similar among individuals with a definite history of vascular disease.

Somewhat in contrast, statin effects in subjects with no known history of vascular disease seemed slightly greater in men (RR 0.72, 99% CI 0.66–0.80) than in women (RR 0.85, 95% CI 0.72–1.00).

Among all 27 trials, statin therapy reduced the risk of major coronary events by 24% for each 1.0-mmol/L reduction in LDL cholesterol, with significant reductions in both women (RR 0.83, 99% CI 0.74–0.93; P<0.0001) and men (RR 0.74, 99% CI 0.70–0.78; P<0.0001). Statin therapy also reduced coronary-revascularization procedures by the same 24% percent for each 1.0-mmol/L drop in LDL cholesterol, again with no significant sex differences evident overall.

The overall proportional reduction of 15% in any stroke for each 1.0-mmol/L reduction in LDL cholesterol (RR 0.85, 95% CI 0.80–0.89) was also similar between women and men and again broadly similar at all levels of CVD risk. Importantly, reductions in major vascular events were also broadly similar irrespective of sex at all levels of CVD risk, including among women and men whose 5-year risk of having a major vascular event was low, at <10%.

Overall, statin therapy also produced a highly significant 12% proportional reduction in vascular mortality (RR 0.88, 95% CI 0.84–0.91) for each 1.0-mmol/L reduction in LDL cholesterol and a nominally significant reduction in deaths from unknown causes.

Finally, after adjustment for non-sex differences, there were similar proportional reductions in all-cause mortality for each 1.0-mmol/L reduction in LDL cholesterol of 10% in men (RR 0.90, 99% CI 0.86–0.95) and 9% in women (RR 0.91; 99% CI 0.84–0.99).

Importantly statin treatment had no significant effect on cancer or cancer mortality, and there was no evidence of any difference in the safety of statin therapy between women and men.

This report is critical to preventative cardiology as we have powerful statins at full dose (Rosuvastatin & Atorvastatin) capable of reducing LDL by 3-4 mmol/L. With statin associated independent reduction of us-CRP (inflammatory marker) we potentially can reduce individual morbidity and mortality by 80%.

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Coupling statin therapy with aggressive lifestyle intervention with appropriate diet, exercise, sleep and stress reduction we can achieve excellent results, particularly in women.

Quote on life

References

  1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: Meta-analysis of individual data from 174,000 participants in 27 randomised trial. Lancet 2015; DOI:10.1016/S0140-6736(14)61368-4

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