This sneaky sign could indicate high cholesterol—are you catching it in your patients?
Key Takeaways
Industry Buzz
"[This symptom] can be easy to brush off as just getting older or being out of shape. But when it keeps happening, it’s often an early sign of PAD that we need to catch before it progresses.” — Raj Dasgupta, MD, FACP, FCCP, FAASM
"Managing cholesterol aggressively is just as important for people with PAD as it is for those with coronary artery disease.” — Gail Clifford, MD, MMM, CPE, FACP, FHM
Find more of your peers' perspectives and insights below.
Steve Hamburger was 63, fit enough for tennis, yet he couldn’t walk more than two blocks before calf pain forced him to stop. An ankle-brachial index and angiogram confirmed peripheral artery disease (PAD), caused by plaque-clogged arteries.[] Intermittent claudication like this is the “classic” presentation of PAD.
PAD is hardly rare. The CDC estimates that approximately 6.5 million adults in the United States aged 40 or older live with the condition, and that as many as 4 in 10 experience no leg pain at all.[]
“One of the most common early signs we see is leg pain or cramping that shows up when someone walks and then goes away after they stop to rest,” says Gail Clifford, MD, MMM, CPE, FACP, FHM, a medical consultant. “Most people assume it is a pulled muscle, arthritis, or just getting older, [but] because it is not constant and goes away with rest, people often do not mention it until it interferes with their routine.”
Raj Dasgupta, MD, FACP, FCCP, FAASM, a board-certified physician, adds, “A lot of patients don’t describe classic ‘pain’ at first. It’s more of a tired, heavy feeling in the calves when they walk ... That can be easy to brush off as just getting older or being out of shape. But when it keeps happening, it’s often an early sign of PAD that we need to catch before it progresses.”
Role of cholesterol
PAD mirrors coronary atherosclerosis: cholesterol-laden plaque narrows large and medium arteries, throttling perfusion. Recent genetic work strengthens the causal link between dyslipidemia and PAD.[] A 2025 Mendelian randomization study involving more than 38,000 individuals with PAD showed that each 39 mg/dL (1 mmol/L) genetically mediated rise in LDL-C increased PAD odds by about one-third, independent of other lipids.
“The connection is powerful,” Dr. Clifford explains. “High LDL cholesterol—and even more so, high levels of ApoB—plays a significant role in plaque buildup in arteries ... Managing cholesterol aggressively is just as important for people with PAD as it is for those with coronary artery disease.”
Dr. Dasgupta echoes this: “LDL-C is our main target, but elevated ApoB levels have been linked to an increased risk of PAD ... While it's a useful test for assessing cardiovascular risk, it's not typically included in routine cholesterol and lipid panels.”
Related: Lipid panels lie: 'It’s time to rethink the way we evaluate CV risk—before it’s too late'Lipidomic work released by the CDC this May reached a similar conclusion, linking multiple cholesterol-containing lipid species to subclinical PAD progression in a longitudinal US cohort.
Both experts also note the rising relevance of other lipid biomarkers. “Lipoprotein(a), or Lp(a), is getting more attention,” says Dr. Clifford. “It has not been routinely tested but may change as targeted therapies become available.” Dr. Dasgupta agrees: “It’s highly atherogenic and often runs in families ... It’s also pushing us to look beyond just LDL-C.”
Why it matters
Physicians need to explain to patients that PAD is not just a limb problem. Large cohort studies show that PAD amplifies cardiovascular risk by roughly two- to three-fold.[] In fact, the current US guidelines classify PAD as a coronary disease equivalent and justify aggressive lipid-lowering once leg symptoms, or ankle brachial index (ABI) screening, uncover the disease.[]
“I like to remind people that PAD is not just about leg circulation—it is a sign of widespread artery disease,” says Dr. Clifford. “If you have PAD, your risk of heart attack or stroke is at least two to three times higher.”
The latest guidelines
An August 2024 American College of Cardiology expert review labeled PAD “a prevalent and severe form of atherosclerotic disease” and urged clinicians to push LDL-C below 70 mg/dL, often with statin plus ezetimibe or PCSK9 inhibition.[] The rationale is simple: Aggressive lipid-lowering curbs both limb loss and major cardiovascular events.
Related: A statin and PCSK9 alternative is on the horizon—here's what we know so far“They are tough, but they are doable,” says Dr. Clifford. “For many patients, high-intensity statins can get us close. If not, we will add ezetimibe or a PCSK9 inhibitor ... We know these targets lower the risk of future events, so I reach them when possible.”
Dr. Dasgupta agrees: “While statins are a first-line therapy, along with lifestyle modifications ... recent guidelines recommend combination therapies ... The good news is we have more tools now.”
In the clinic
Dr. Clifford emphasizes: “If someone comes in describing leg pain that starts with walking and goes away with rest, I almost always order an ankle-brachial index... I also order it for people who are at high risk—even if they aren’t complaining of symptoms yet.”
Dr. Dasgupta adds, “I usually go straight to the ABI... and if they have major risk factors like diabetes or a history of smoking, I won’t wait for symptoms.”