Larence Leiter, MD, is the director of the Lipid Clinic and associate director of the Clinical Nutrition and Risk Factor Modification centre at St. Michael’s Hospital in Toronto.

Lawrence Leiter, MD

Lawrence Leiter, MD | Image Credit: University of Toronto

Intensive LDL-C lowering has reshaped secondary prevention over the past decade, with large randomized trials consistently demonstrating incremental cardiovascular benefit as achieved 

 falls below previously accepted thresholds. The FOURIER trial enrolled 27,564 patients with established 

atherosclerotic cardiovascular disease (ASCVD)

 on background statin therapy and randomized them to the PCSK9 inhibitor evolocumab or placebo, reducing median LDL-C to 30 mg/dL and reducing the risk of major adverse cardiovascular events. Long-term follow-up data from FOURIER-OLE, extending some patients' exposure to nearly 8 years, showed sustained event reduction including, for the first time with this drug class, a significant reduction in cardiovascular death.

The evidence now points toward earlier, more aggressive intervention. A 2024 meta-analysis of 60 randomized controlled trials found the hazard ratio per 1 mmol/L LDL-C reduction was more favorable in primary prevention (0.74) than in secondary prevention (0.80), suggesting greater proportional event reduction is achievable before atherosclerotic burden accumulates. For patients with 

, the risk calculus is further complicated by persistent residual cardiovascular risk: the ADA's 2026 Standards of Care reaffirm LDL-C lowering as central to ASCVD risk reduction in this population, with benefit directly proportional to the magnitude of LDL-C reduction across statin and nonstatin regimens.

Lawrence A. Leiter, MD, director of the Lipid Clinic and associate director of the Clinical Nutrition and Risk Factor Modification Centre at St. Michael's Hospital in Toronto, has contributed to multiple FOURIER analyses and brings particular expertise to the intersection of lipid management and diabetes. In the following interview, Lawrence A. Leiter, MD, spoke with HCPLive at the 

 in Philadelphia about LDL-C target achievement, sequencing of nonstatin therapies, and multifactorial risk reduction in patients with diabetes.

Q&A: Intensive LDL Lowering and Cardiovascular Prevention Strategies, With Lawrence Leiter, MD

HCPLive: In high-risk patients with diabetes who do not have established ASCVD, what defines the threshold for moving to PCSK9 inhibition rather than intensifying conventional lipid-lowering therapy?

I think the key point, what the evidence shows us, is that intensive LDL lowering and getting to targets lower than had been previously recommended is associated with significant cardiovascular benefit. The training, the VESALIUS-CV trial I was involved with, we used a PCSK9 inhibitor, evolocumab, in patients who had elevated LDL, despite optimized statin therapy. But when we translate in the real world, I think the key is the achievement of a lower LDL target, not the drugs that were specifically used. If patients aren't starting off with as high LDL as we had in VESALIUS-CV, often one can get them to a target of <55 or 40, as we did in the trial mix per deciliter with statins plus or minus ezetimibe plus or minus bempedoic acid, and only if you don't get them there with those agents, is it necessary to move on to a PCSK9 inhibitor?

HCPLive: Do you see the expanding use of PCSK9 inhibition in high-risk diabetes as a shift towards preemptive ASCVD disease modification?

Well, I think we know it's easier to prevent disease than it is to treat it when it's already present. First of all, looking at the big picture, there are far too many patients we see whose first symptom is their last symptom. Patients who had unrecognized atherosclerosis have an MI and may pass away as a result of that. We cannot wait until people have significant atherosclerotic burden and only start to treat then – we need to prevent it earlier. I think we now know that for the same magnitude of LDL cholesterol reduction you're going to see greater event reduction in people who have not yet had an event, so-called primary prevention population, than those who already did. That's presumably because it's easier to prevent plaque from occurring rather than waiting until a person has significant plaque in their coronary arteries and only then intervening.

HCPLive: Are we approaching a point in which lipid lowering in diabetes is viewed as a foundational risk reprogramming?

Well, our patients with diabetes continue to have increased cardiovascular risk, and even the latest data would show that our patients with diabetes continue to have twice the cardiovascular risk as people without diabetes, and there isn't going to be a single intervention that is going to reduce that risk. We really need a multifactorial risk reduction strategy. It's difficult, and patients will push back against polypharmacy, and often it's a negotiation for each additional drug we need to add. But to me, optimizing all the risk factors is foundational. We have to improve their glucose, improve blood pressure, optimize lipids, use other evidence-based therapies, SGLT2 inhibitors, GLP-1 RAs, aspirin as appropriate. There are many things we need to do to significantly reduce the risk in our patients with diabetes.

Editors’ Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. 

Brouwers JJWM, Koopal M, Visseren FLJ, et al. Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 60 randomized controlled trials. Atherosclerosis. 2024;395:118540. 

doi:10.1016/j.atherosclerosis.2024.118540

American Diabetes Association. 10. Cardiovascular disease and risk management: standards of care in diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S216-S266. 

https://pubmed.ncbi.nlm.nih.gov/41358899/

Articles

Intensive LDL-C lowering to levels near 30 mg/dL with PCSK9 inhibition has delivered sustained MACE reductions and, with prolonged exposure, cardiovascular mortality benefit. Meta-analytic data indicate larger proportional risk reductions in primary versus secondary prevention, supporting earlier intervention before plaque burden accrues. In diabetes, persistent residual ASCVD risk makes LDL-C lowering a central, dose-responsive strategy across statin and nonstatin regimens. Practical sequencing emphasizes achieving stringent LDL-C targets (eg, <55 or <40 mg/dL) using statins, ezetimibe, and bempedoic acid before escalating to PCSK9 inhibitors.

Leiter discusses the importance of earlier and more dramatic lipid-lowering interventions in patients with diabetes at risk of cardiovascular disease.