Summary of Looking Beyond Statins For New Ways To Lower Cholesterol

Overview of Looking Beyond Statins For New Ways To Lower Cholesterol

This Science Friday episode (host Ira Flatow) features cardiologists Dr. Neha Pagidipati (Duke) and Dr. Kiran Musunuru (University of Pennsylvania). They review how clinicians decide who should take statins, explain how statins work and their side effects, evaluate diet and newer lipid-lowering options (PCSK9 antibodies/siRNA), discuss the cardiovascular effects of GLP-1 drugs, and describe emerging one‑time gene‑editing (CRISPR) approaches to lower LDL for life. The conversation balances current clinical practice, alternatives for statin‑intolerant patients, and the promise and caveats of gene editing.

Main takeaways

• Statins remain first‑line therapy: robust evidence from large trials shows statins lower LDL, reduce heart attacks/strokes, and improve survival.
• Treatment decisions use guidelines and risk calculators (10‑year risk), but physician judgment and patient preferences matter; imaging (coronary calcium) can refine decisions, especially for younger patients.
• True statin‑induced severe muscle damage is rare; many perceived muscle symptoms are likely nocebo effects.
• Alternatives for statin‑intolerant patients include PCSK9 monoclonal antibodies (biweekly injections), inclisiran (siRNA, ~every 6 months), and other oral/biologic agents.
• Diet/lifestyle matter but usually produce modest LDL reductions compared with pharmacologic therapy; Mediterranean and DASH diets have the strongest evidence.
• GLP‑1 receptor agonists (weight‑loss/diabetes drugs) produce modest improvements in LDL/HDL/triglycerides — weight loss explains much of that — and their cardiovascular benefits are not primarily via lipid lowering.
• Gene editing (targeting PCSK9 and other liver genes) is in early clinical trials. Initial results show large, durable LDL reductions (50–70%), but long‑term safety and cost remain open questions. Some experts expect approved gene‑editing lipid therapies to appear in the 2030s.

How clinicians decide who needs a statin

• Guidelines: major professional societies provide evidence‑based recommendations. Indications include secondary prevention (prior heart attack/stroke/stent) — essentially all such patients should be on lipid‑lowering therapy.
• Primary prevention: use 10‑year risk calculators (cholesterol, blood pressure, diabetes status, smoking). These calculators may underrepresent some populations (ancestry/family history) and often miss younger people who have high lifetime risk but low 10‑year risk.
• Shared decision‑making: because risk thresholds can be subjective, physicians and patients discuss tolerability, preferences, and other risk‑modifying data (e.g., coronary artery calcium scoring) to decide when to start therapy.

How statins work and what they do

• Mechanism: statins inhibit a key liver enzyme in cholesterol synthesis, lowering circulating LDL cholesterol.
• Effects beyond LDL: there may be additional (pleiotropic) benefits such as reduced vascular inflammation, but the primary proven mechanism of benefit is LDL reduction.
• Outcomes: statins reduce heart attacks, strokes, and all‑cause mortality based on decades of trials and hundreds of thousands of patients.

Side effects and true statin intolerance

• Muscle symptoms: true statin‑induced myopathy or rhabdomyolysis is uncommon. Many reported aches may be due to the nocebo effect or normal age‑related aches.
• Pattern of medication‑related myopathy: typically symmetric, proximal muscle groups (thighs, buttocks, shoulders), not isolated fingertip or asymmetric pain.
• Management: if true intolerance exists, alternatives (PCSK9 inhibitors, inclisiran, other oral agents) are available.

Diet, lifestyle, and cholesterol

• Diet influences LDL but effects are typically modest compared with medication. Large sustained dietary trials are difficult to run, so evidence is more limited than for drugs.
• Evidence‑backed eating patterns: Mediterranean diet (good randomized data) and DASH (especially for blood pressure) are recommended for cardiovascular risk reduction.
• Saturated fat: experts in this episode strongly disagree with claims that saturated fat is “okay.” High saturated‑fat diets (e.g., some ketogenic diets) can cause very high LDL in some people.

Newer and alternative lipid‑lowering therapies

• PCSK9 monoclonal antibodies: injectable biologics (every 2 weeks or so) that substantially lower LDL and are effective alternatives for those who can’t tolerate statins or need additional lowering.
• Inclisiran (siRNA): targets PCSK9 in the liver with dosing about every six months; useful for maintenance therapy.
• Oral agents and other classes are also in development.

Gene editing (CRISPR) for lifelong LDL lowering

• Rationale: loss‑of‑function variants in genes such as PCSK9 occur naturally in ~2–3% of people and are associated with an ~80–90% reduction in heart disease risk. This suggests turning off these genes is protective.
• Approach: use CRISPR or other gene‑editing technologies targeted to the liver to permanently reduce PCSK9 (or other targets) expression — potentially a one‑and‑done therapy.
• Early clinical experience: gene‑editing lipid trials began around summer 2022. Early results show large (50–70%) LDL reductions that appear durable, but follow‑up is limited.
• Concerns: long‑term safety (off‑target effects), cost, ethical/regulatory issues, and the need for large long‑term outcome data. Several companies are pursuing different gene‑editing approaches; approvals may arrive in the 2030s.

GLP‑1 receptor agonists and lipids

• Effect on lipids: GLP‑1 drugs (and related agents) cause weight loss that modestly lowers LDL, raises HDL slightly, and lowers triglycerides — but lipid changes are small relative to statins/PCSK9 therapies.
• Cardiovascular benefits of GLP‑1s are real but likely mediated by multiple mechanisms (weight loss, glucose control, blood pressure, inflammation), not solely lipid lowering.

Practical recommendations / action items for listeners

• If concerned about cholesterol/risk: ask your clinician about your 10‑year and lifetime cardiovascular risk and whether a coronary artery calcium (CAC) scan would change management.
• If started on a statin and have symptoms: discuss symptom pattern with your doctor — many symptoms are unrelated, and true myopathy is rare. Consider a supervised re‑challenge or alternative dosing/agents if needed.
• For those reluctant to take meds: adopt evidence‑based diets (Mediterranean/DASH), increase physical activity, and address other risk factors (blood pressure, diabetes, smoking).
• If statin‑intolerant or requiring more LDL reduction: ask about PCSK9 inhibitors or inclisiran; discuss eligibility and cost/coverage.
• For patients interested in cutting‑edge options: gene‑editing therapies are experimental; ask about clinical trials at major centers if you are eligible, but be aware long‑term safety and access remain unresolved.

Notable quotes & figures

• “About 2–3% of the population has naturally occurring variations that turn off PCSK9…they have dramatically reduced risk of heart disease, something like 80 to 90 percent reduced risk.” — Dr. Kiran Musunuru
• “Statins will reduce the risk of heart disease…many studies…collectively hundreds of thousands of patients…they reduce the risk of heart disease.” — Dr. Kiran Musunuru
• Early gene‑editing trials report LDL reductions of 50–70% and appear durable so far (clinical trials started ~summer 2022).

Guests and production

• Guests: Dr. Neha Pagidipati (Preventive Cardiologist, Duke University) and Dr. Kiran Musunuru (Cardiologist, Univ. of Pennsylvania).
• Host: Ira Flatow. Episode produced by Anita Heist.

This summary highlights clinical practice today, practical alternatives for statin intolerance, dietary context, and the promise — plus caveats — of one‑time gene‑editing therapies that could reshape future cholesterol management.