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Peter Attia MD#07 – Deep Dive: Lp(a) — what every doctor, and the 10-20% of the population at risk, needs to know
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CHAPTERS
- 0:04 – 4:33
Why Lp(a)? Poll results and episode format
Peter Attia explains that a Twitter poll ended roughly 80/20 in favor of Lp(a) over hormone replacement therapy. He describes the interview format with Bob and notes the show notes pictures will help with the technical material.
- •Poll result was about 80% for Lp(a) versus HRT
- •HRT is promised for a future episode
- •Bob interviews Peter with questions sent in by listeners
- •Show notes images help with kringle structure details
- 4:33 – 11:00
Lipoprotein primer: cholesterol, LDL, HDL and ApoB
Peter gives a primer on lipoproteins. Cholesterol must be packaged in water-soluble particles to travel in blood, and a standard lipid panel reports cholesterol content rather than particle number. He covers ApoB, particle counts and how atherosclerosis begins through retention in the subendothelial space.
- •Cholesterol is needed for cell membranes and hormones
- •Lipoproteins carry cholesterol through the watery blood
- •LDL-C measures cholesterol content, while LDL-P and ApoB track particle number
- •Each LDL particle has one ApoB 100, while HDL carries ApoA1
- •Risk arises when particles are retained, oxidized and trigger inflammation
- 11:00 – 20:23
What is Lp(a)? Structure, kringle domains and the New York Times story
Bob cites a New York Times article about Bob Harper's heart attack as a driver of interest. Peter describes Lp(a) as an LDL particle with Apo(a) attached to ApoB by a disulfide bond, with kringle repeats resembling plasminogen. Every Apo(a) sits on an LDL, but not every LDL has one.
- •The article described Bob Harper's heart attack and high Lp(a)
- •Roughly one in five to one in ten people have elevated Lp(a)
- •Apo(a) is covalently bound to ApoB and resembles plasminogen
- •Kringle IV type 2 repeats vary and determine particle mass
- •Number of Lp(a) particles probably matters more than their mass
- 20:23 – 29:20
How Lp(a) is measured: mass, cholesterol and particle number
Peter and Bob discuss the ways Lp(a) is quantified. Mass is the most common but can mislead because of variable Apo(a) size, and Lp(a) cholesterol is of little use. Peter prefers particle number in nmol/L and explains why a molecular weight conversion isn't possible.
- •Lp(a) mass is most common but can mislead
- •Lp(a) cholesterol is problematic because molecular weight is unknown
- •Peter prefers particle number, wanting under 50 nmol/L, with 50-100 a gray area and over 100-125 worrying
- •Oxidized phospholipid normalized to ApoB is a proxy
- •Apo(a) is rich in lysine, which binds oxidized moieties
- 29:20 – 34:16
Clinical clues and the evolutionary role of Lp(a)
Peter describes the patient picture that suggests elevated Lp(a), such as premature disease without classic risk factors, and defines premature events. Bob then asks why Lp(a) exists, and Peter speculates about clotting benefits and scavenging of oxidized phospholipids.
- •Premature disease without classic risk factors hints at high Lp(a)
- •Patients with the same level can have very different family histories
- •Hypercoagulability could have helped with trauma and childbirth
- •Lp(a) may scavenge oxidized phospholipids and carry them to the liver
- •In today's environment these traits may be overwhelmed
- 34:16 – 40:36
Harms of elevated Lp(a): atherosclerosis, aortic stenosis and venous thrombosis
Peter lays out three categories of harm: enhanced atherosclerosis, aortic stenosis and venous thrombosis. He describes screening for aortic stenosis, the open question of causality that the antisense trial may answer, and his approach to aspirin and flight prophylaxis.
- •Elevated Lp(a) is estimated to explain about two-thirds of aortic stenosis
- •Patients with elevated Lp(a) are screened with echo or cardiac MRI
- •It is not yet proven whether Lp(a) is cause or consequence of atherosclerosis
- •Baby aspirin helps only a subset
- •DVT prophylaxis and Flight Tabs are considered for long flights
- 40:36 – 44:44
Quantifying risk and why doctors need to know
Peter gives hazard ratios for aortic stenosis, VTE and atherosclerosis and explains absolute versus relative risk. He argues atherosclerosis matters most because it is so common, and he is surprised how many front-line doctors lack understanding of Lp(a).
- •Aortic stenosis hazard ratios range from two to four, VTE about three
- •Atherosclerosis risk shows a dose response, about 60% higher at 200 mg/dL
- •A modest relative increase in a common disease is the biggest concern
- •Primary care, family and GYN physicians should understand Lp(a)
- 44:44 – 46:27
Defining elevated Lp(a) and apheresis
Cutoffs are based on mass, with US, European and UK/German thresholds differing. Peter explains apheresis, which can remove Apo(a) but must be repeated very often.
- •US normal is under 30 mg/dL and European under 50 mg/dL
- •UK and Germany consider over 60 enough for state-covered apheresis
- •Apheresis separates plasma and removes the target
- •Particle half-life means treatment might be needed twice weekly
- 46:27 – 56:17
Treatment options: niacin, statins and PCSK9 inhibitors
Peter reviews treatments, starting with niacin and the debate over its value. He explains why statins don't lower Lp(a), and how PCSK9 inhibitors lower it by about 30-50%. Statins are still used to hit an LDL-P target.
- •Niacin lowers Lp(a) by about a third but lacks outcome data
- •Statins don't reduce Lp(a) and may raise it
- •PCSK9 inhibitors give roughly 30-50% reductions but are not approved for Lp(a)
- •Statins remain important for controlling ApoB
- •Patients with high Lp(a) get a lower LDL-P target
- 56:17 – 1:00:35
Estrogen therapy and antisense oligonucleotides
Bob raises a UpToDate note that estrogen replacement may lower Lp(a), which Peter finds surprising. Peter then describes antisense oligonucleotides, the first therapy designed to lower Lp(a) by blocking Apo(a) synthesis, now in phase three trials.
- •UpToDate reports estrogen reduces Lp(a) by up to 50%, but HRT is not recommended for CV risk reduction
- •Peter was skeptical and plans to check menopausal patients
- •ASOs block Apo(a) production in the liver
- •Reductions of 70% to 99% are cited
- •The trials should clarify true risk
- 1:00:35 – 1:09:15
Lifestyle effects, saturated fat and ketogenic diets
The two discuss why Lp(a) barely responds to lifestyle, since production dominates, in contrast to triglycerides and LDL-P. They share experiences of high LDL-P on ketogenic diets with saturated fat, and Peter describes replacing it with monounsaturated fat.
- •Triglycerides respond strongly to diet but Lp(a) does not
- •Lp(a) is driven mainly by how much is made
- •Some people see LDL-P soar on high saturated fat
- •Swapping saturated for monounsaturated fat lowered LDL-P in nearly all of Peter's cases
- •Rising oxidized LDL and CRP suggest inflammation
- 1:09:15 – 1:16:15
Oxidized LDL, local inflammation markers and closing thoughts
Peter distinguishes the OxLDL assay from oxidized phospholipid measures and explains using several markers to judge vascular inflammation. After a J-curve aside, the two reflect on how little is known and Peter urges patients and physicians to pay attention to Lp(a).
- •OxLDL is separate from oxidized phospholipid assays
- •Lp-PLA2 and OxLDL are local inflammation markers
- •Peter says patients should demand to know their Lp(a)
- •An ICD-10 code was recently issued for elevated Lp(a)
- •Peter says his understanding relative to the known unknowns has shrunk
