Do peripheral artery disease risk factors impact men and women differently?

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMOct 20 2023

A recent study published in the PLOS One Journal explored sex differences in how major risk factors relate to hospitalization or mortality due to incident peripheral artery disease (PAD) and whether these sex-based disparities vary across different subpopulations.

Study: Sex differences in risk factors for incident peripheral artery disease hospitalisation or death: Cohort study of UK Biobank participants. Image Credit: Anshuman Rath/Shutterstock.com

Background

Peripheral artery disease (PAD) affects well over 235 million people globally. There is no significant difference between the sexes in the number of total or new cases of PAD per unit population. However, the outcomes tend to be worse in women than men for multiple reasons.

A recent study explores the differences in risk posed by various risk factors for new PAD and its outcomes in men and women.

PAD in men is typically diagnosed following the appearance of intermittent claudication, but in women, the leg symptoms are atypical or absent, causing delayed presentation. This, coupled with a more rapid decrease in function and a greater loss of mobility, results in a worse outcome than in men.

Indeed, surgery for PAD in women is associated with a higher risk of death overall than in men. However, this could be traceable to the later stage at which women present, causing them to develop more severe limb ischemia before treatment than men.

Earlier studies have revealed sex-dependent differences in the risk of stroke, heart attacks, and dementia with the same risk factors.

The study used data from the UK Biobank, including over 500,000 participants. Their mean age was 57 years. None had a history of previous hospitalization.

The participants were examined for hypertension, diabetes, smoking, abnormal lipids, increased body fat mass, and a prior stroke or heart attack history.

They were also tested for renal function and inflammation (C-reactive protein levels), and their socioeconomic status and alcohol consumption levels were determined.

What did the study show?

The median period of follow-up was ~13 years. During this period, new PAD was found to affect over 2,500 women and 5,000 men, causing either hospitalization or death.

Among men, there were ~19 new cases per 10,000 person-years (PYs), vs 8 among women, showing a more than doubled incidence. Even after adjusting for age, the men were found to have higher rates of new cases despite compensating for other risk factors.

Excess risk – women

Smokers and those with a previous stroke or heart attack were more likely to develop PAD compared to others who did not have these risk factors. Among current smokers, women had a 20% excess PAD risk.

Compared to never-smokers, the excess risk was 20% higher for women at the highest levels of smoking (20 or more cigarettes a day) compared to men.

With a previous stroke, the excess risk for women went up by a quarter and by half if the woman had a prior heart attack. The risk for PAD was more than tripled in women with a previous stroke compared to those without, vs 2.7-fold in men. With a prior heart attack, women were at a fivefold risk for PAD compared to others, vs tripled risk in men.

Only high-density lipoprotein (HDL) was associated with an inverse PAD risk among the various cholesterol fractions. With each increase by one mmol/L, the risk decreased by 44% and 20% in women and men, respectively, with the reduction being 34% more among women.

Among both sexes, individuals with the lowest HDL levels, at less than 40 mg/dL, were at higher PAD risk than if the levels were between 40 and 60 mg/d. Women showed 20% excess risk compared to men.

For overweight people, the PAD risk was 20% higher in women than men. Both sexes showed a higher risk with increasing deprivation, though women had lower excess chance at the lowest socioeconomic levels.

Current alcohol consumption was linked with a 30% to 40% reduction in PAD risk, with women showing a 25% lower risk than men in both daily and once-a-week drinking categories.

Excess risk – men

Among past smokers, the risk for women was 60% higher than never smokers but doubled in men, so men had an excess risk of 20%.

Conversely, women with the highest HDL levels, at over 80 mg/dL, had a 20% lower PAD risk, in contrast to a 60% higher risk among men. Thus, the risk of PAD with high HDL was 50% lower for women than men. The rise in HDL showed a log-linear inverse association with PAD risk in women vs a U-shaped curve in men.

Among overweight people, for each increase of 0.1 in the waist-hip ratio, the risk increased by 15% more in men than women.

Excess risk – comparable

Both type 1 and type 2 diabetes increased the risk of PAD by fivefold and twofold, respectively, in both sexes, as did high blood pressure.

PAD risk was also associated with increased fat mass, with the risk increase being comparable between the sexes. A decline in kidney function and inflammation, were both associated with a higher risk of PAD in both sexes.

What are the implications?

With some risk factors, namely, smoking and prior heart attack or stroke history, the PAD risk was higher among both sexes, but more so for women. In contrast, high HDL cholesterol levels were linked to a higher risk of PAD for men than for women.

An earlier study showed the opposite trend with smoking-associated PAD risk among men, perhaps because of increased smoking among men, but comparable quitting durations among both sexes.  

Further research is required to understand the exact impact of high blood pressure on PAD risk in women because this study shows a log-linear increase in risk with higher systolic blood pressure at all values, but only from 140 mm Hg in men. This contradicts an earlier study which found no sex difference in the increased PAD risk with systolic blood pressure.

The current study reported only on hospitalized and fatal PAD cases, probably underestimating the actual incidence, though more accurately representing the healthcare burden on the system and patients.

The findings suggest that women at risk for PAD should be encouraged to stop smoking and that the index of suspicion should be high in women with a prior history of cardiovascular events. The presence of overweight, especially among women from more deprived environments, should also be considered.

“If the observed doubled risk of PAD documentation in men than women are due to sex differences in symptoms, identifying risk factors could benefit affected asymptomatic women.”

However, more evidence is required to validate these results.