The Curbsiders Internal Medicine Podcast

Episode #508: ASCVD Risk & Lipids Update! PREVENT, ApoB, Lp(a) + Next-Gen Therapies
Date: December 15, 2025
Guest: Dr. Lawrence (Larry) Sperling, Katz Professor at Emory, CMO of the Family Heart Foundation

Episode Overview

This episode delivers an up-to-the-minute review of atherosclerotic cardiovascular disease (ASCVD) risk assessment, lipid management, and next-generation therapeutics. Dr. Lawrence Sperling, world expert in preventive cardiology, guides listeners through nuanced risk prediction methods (including the PREVENT calculator), underutilized labs like ApoB and Lp(a), practical application of non-statin therapies, the growing role of genetics, and patient-centered approaches to cardiovascular prevention. The discussion is woven with clinical pearls, memorable analogies, and a focus on real-world implementation.

Key Discussions & Insights

1. The Art and Science of ASCVD Risk Assessment

- The Foundational “CPR” Approach to ASCVD Risk

• Calculate risk with validated risk scores
• Personalize risk: layer in "risk enhancers" such as family history, metabolic syndrome
• Reclassify risk with additional tools (e.g., coronary arterial calcium, further labs)

Key Quote:

“CPR: Calculate, Personalize, Reclassify. Risk assessment is not the end—it’s the beginning of clinical decision making.”
– Dr. Sperling [11:44]

[08:39–14:43] Case Example: 52-year-old man with metabolic syndrome

• Non-HDL cholesterol is a critical, underused measure—additive value, no extra cost.
• Cardio-metabolic risk should be explicitly discussed as it broadens the prevention lens to diabetes and other manifestations.

2. Lab Pearls: Non-HDL, ApoB, and Lp(a)

A. Non-HDL Cholesterol

• Simple calculation: total cholesterol minus HDL = non-HDL (captures all atherogenic particles)
• "Do the Math": It's free, comes with every lipid panel.
• Target: For LDL goal <70 mg/dL, non-HDL goal <100 mg/dL ([34:15]).

B. ApoB: When and Why? [26:29–34:41]

• Scientifically more accurate for atherogenic risk, but not front-line for all.
• Most helpful when:
  • Triglycerides are significantly elevated
  • Discordance between LDL and ApoB suspected (rare: ~2% of cases)
  • LDL is very low (<70 mg/dL) on therapy or calculation becomes unreliable (even negative)
• Overuse can confuse patients; focus currently is on improving care with existing LDL targets.

Key Quote:

“Our biggest challenge today is not scientific knowledge—it’s implementation. I’m a selective user of ApoB.”
– Dr. Sperling [28:56]

C. Lp(a): The "Triple Threat" Lipoprotein [36:34–41:37]

• Increases risk through: atherogenicity, inflammation, and thrombosis
• 1 in 5 globally have high Lp(a), higher prevalence in women, Black, South Asian populations.
• Universal screening is done in Canada, Europe; rare (<1%) in US but may soon change.
• Reporting: measured as nmol/L (preferred) or mg/dL; standardization needed.
• Strong familial/genetic component—screen patients/families with early heart disease.

Key Quote:

“Lp(a) is a triple threat—atherogenic, inflammatory, and prothrombotic. We underappreciate its clinical value.”
– Dr. Sperling [36:36]

3. Using Coronary Calcium and Risk Reclassification [15:21–23:56]

• When to consider coronary calcium scoring:
  • As a second step for patients with intermediate risk or unclear decision on statin initiation
  • Not appropriate in very low- or very high-risk patients
• Important counseling:
  • “A score of zero is reassuring, but not an absolute guarantee—could still be non-calcified plaque.”
  • Adjust interpretation for age, gender, ethnicity (MESA tables).
• CCTA (coronary CT angiography): promising, not yet standard for primary prevention.

4. PREVENT Risk Calculator [42:00–48:51]

What’s Different and Why Now?

• Broader age (30–79 years), includes BMI, eGFR, diabetes.
• Uses zip code (social deprivation index) instead of race.
• 10- and 30-year (lifetime) risk estimation.
• Allows “total CVD,” heart failure prediction.
• More accurately calibrated: likely that future statin thresholds will be lowered (e.g., ~3%) based on PREVENT.

Key Quote:

“PREVENT lets us move beyond 10-year risk to 30-year, lifetime risk—and eliminates race as a factor.”
– Dr. Sperling [45:54]

5. Statins, Shared Decision Making & Side Effects [50:39–57:56]

• Explain statins as “CVD risk reducers,” not just as “cholesterol meds.”
• Discuss anticipated benefit, common side effects (myalgias, not true myositis), and risk of not starting.
• Use ultra-low, intermittent dosing where needed (e.g., rosuvastatin every other day).
• Emphasize “the right statin for the right patient” and revisit decisions longitudinally.

Notable Moment:

“For every medicine, we consider indications, contradictions, benefits. We also must weigh the risks of not starting.”
– Dr. Sperling [51:51]

Lifestyle Modification

• Dietary pattern over “diet”—preferably Mediterranean, flexitarian, or “portfolio” (more nuts, oat bran, flax, high-quality dark chocolate [~65% cacao+]).
• Most patients will see modest (<10%) LDL reduction from diet alone.
• For overt familial hypercholesterolemia (FH): immediate medication plus lifestyle (don’t delay).

6. Familial Hypercholesterolemia (FH) and Family Cascade Screening [73:56–88:09]

• Suspect FH in patients with very high LDL (>190 mg/dL) at a young age—especially if family history of early CV events.
• Non-response to max statin/ezetimibe often signals monogenic causes (e.g., LDL-R, ApoB, PCSK9 mutations).
• Physical signs: corneal arcus, xanthelasma, tendinous xanthomas.
• Cascade family screening and consider genetic testing (over 2,000 FH variants described).

Key Quote:

“If you’ve ruled out secondary causes and LDL is >190, don’t bother with risk calculators—go straight to therapy.”
– Dr. Sperling [77:54]

7. Non-Statin and Next-Gen Therapies [81:01–91:52]

Bempedoic Acid

• ACL inhibitor, modest LDL lowering (~20–30%)
• Event reduction shown (CLEAR Outcomes), but not mortality

PCSK9 Inhibitors (alirocumab, evolocumab)

• Potent; first-line non-statin add-on for FH or very high risk

Inclisiran

• siRNA against PCSK9, dosed twice yearly. Awaiting outcome trial data.

Lipoprotein Apheresis

• Reduces time-averaged LDL/ApoB/Lp(a) by up to 80%, considered in severe FH or when refractory to usual therapy.

Lp(a) Lowering Drugs

• Pelacarsen and others: Early trials show 80–100% Lp(a) lowering; outcomes trials now underway (HORIZON trial, etc.).
• Hopeful, but surrogate markers—need confirmation of hard endpoint benefits.

8. Pearls on Patient Conversation and Prevention Philosophy

Memorable Moment:

• Dr. Sperling's contract analogy for prevention:

“We sign a contract to age 100, and then renew one year at a time. This is a partnership—you get more votes than me, you’re the patient.” [13:53]

On Early Statin Use and Lifetime Risk:

• “Cholesterol years” matter—prolonged exposure increases cumulative risk. Discuss with younger, high-risk patients (esp. with strong family history).
• Ok to defer 3 months for lifestyle change in primary prevention if risk is not extreme.

Timestamps for Key Segments

• Career & Advice: [05:30–07:22]
• Case 1 Discussion (ASCVD Risk): [08:39–14:43]
• Coronary Calcium Scoring & CCTA: [15:21–23:56]
• ApoB & Discordance: [26:29–34:41]
• Lp(a) in Practice: [36:34–41:37]
• PREVENT Risk Calculator: [42:00–48:51]
• Statin Counseling & Lifestyle: [50:39–62:56]
• Familial Hypercholesterolemia, Genetics: [73:56–88:09]
• PCSK9, Bempedoic, Inclisiran, Apheresis: [81:01–88:09]
• Lp(a) Lowering Trials—Future Outlook: [88:54–91:52]
• Take-Home Message: [92:36–93:42]

Take-Home Clinical Pearls

• Risk assessment is the gateway, not the gatekeeper—partner with patients over time.
• Don’t ignore non-HDL cholesterol—calculate and act on it!
• Screen for Lp(a) at least once, especially with family history, early disease, or intermediate risk.
• PREVENT risk calculator will likely reshape practice—get familiar and be ready for lower medication thresholds.
• FH is underdiagnosed—look for it, confirm, and screen families.
• Statin “intolerance” is rare; use creative dosing and frame benefits as CVD protection, not just cholesterol-lowering.
• Non-statin and next-gen therapies are expanding options, especially for genetic hyperlipidemias and soon, elevated Lp(a).

Memorable Quotes

“Each visit doesn’t have to be an all-or-none statin decision. Plant seeds. Patients will often circle back when they’re ready.”
– Dr. Sperling [54:53]

"My job is never to convince you to take a medicine … but to translate the evidence for you."
– Dr. Sperling [56:51]

“We’re devoted to cardiovascular disease prevention, which is very possible today and will have greater possibilities in the future.”
– Dr. Sperling [93:36]

This summary captures the clinical depth and spirit of the episode—useful as a reference for patient care or board review, and perfect for those who want high-yield pearls without listening to the full podcast.