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Cardiovascular Disease

The following transcript has been edited for clarity and length.

, a website for primary care physicians. Today I'm speaking with Dr. Patrick Moriarty about cardiovascular risk and risk assessment. More specifically, we're going to talk about the evidence for the role of lipoprotein A, which I will call Lp(a) here on, as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and as a target for therapy. Dr Moriarty is a professor in the Department of Internal Medicine at the University of Kansas Medical Center in Kansas City, where he is also the Director of Clinical Pharmacology and the Atherosclerosis/Lipoprotein-Apheresis Center. He'll be speaking on this topic that we're talking about today, next week at the 2020 virtual Cardiometabolic Health Congress. Welcome Dr. Moriarty. 

 Thank you Grace for inviting me. Good afternoon to you.

 Thank you. So, you're involved in the most current research on the role of Lp(a) in the development of ASCVD and also in some promising research on a potential treatment to reduce levels in patients at high risk. Could you just give us a little bit of background on how Lp(a) became identified as one of the more important markers of residual cardiovascular risk?

 Sure. It goes back all the way to 1963. A Dr. Berg from Norway - he was a physician but also a researcher - was trying to investigate if there were new blood types. In his investigation, he immunized rabbits with a human beta lipoprotein from a single donor. The antibodies that he found that developed from this procedure, were found in one-third of the population. And eventually he found out that these patients that had this protein, had an increased risk of cardiovascular disease and he called it lipoprotein A, and that's where it originated from. So, we're going all the way back there, and it's progressing and progressing up until now. If you want, I can give you a quick overview of what this lipoprotein is.

 It contains an LDL-like moiety 100 in size, like a typical LDL. It has this apolipoprotein A bound to it and this apolipoprotein A looks somewhat like plasminogen, except it doesn't have an active protease domain. The protease domain of plasminogen is what causes clots to break up because our blood is constantly clotting or unclotting, daily, if not we would bleed to death or we'd clot to death. So, this plasminogen goes to where a clot is and breaks it up. Well, Lp(a) goes where it is, binds to it, but does not increase the fibrinolytic cascade. The clot sustains a longer duration, which in places like cardiac and brain, could be very detrimental. Third, it’s a major carrier of inflammatory molecules, including, more importantly, oxidized phospholipids. About 80% of our oxidized phospholipids in the blood are carried on this lipoprotein. And oxidized phospholipids are major players in the plaque foam cell deposition and degradation of plaque causing rupture, which is a major etiology of a cardiovascular event is a ruptured plaque. So, it's a triple whammy because it has LDL too. It's LDL, inflammation, and coagulation. About a third—20% to 30%—of the world’s population have this lipoprotein, and you're born with it. It's an autosomal dominant gene that dictates it. So, if you have it, 50% chance your children might have it. And you can't change it by lifestyle, diet, exercise has no effect on it. Actually, statins might raise it a certain percentage. Well, the good thing about that, even though statins do raise it, the statins still give clinical benefit. There was a study called JUPITER where they used rosuvastatin—if you remember that—and it was a primary prevention study and they showed a reduction in cardiovascular events and reduction of LDLs quite dramatically, but then they looked back and said "okay, what about the patients in that trial that had a high Lp(a)?" Well, they showed that they still got benefit with the statin, but it was attenuated. It was weakened by the high Lp(a), so you never stop a statin therapy in a patient based on their Lp(a) level.

 This new molecule, I believe it's an antisense oligonucleotide, is what you were looking at in your research that was published in the beginning of the year. What is it? And how does it work?

 We published a paper in January of this year in the 

. It was a phase 2 trial where we had different levels of this drug dosing in patients, about 85% got some dose and 15% got placebo; and it's an antisense oligonucleotide, as you mentioned. Present day monoclonal antibodies, such as the PCSK9 inhibitors, inhibit the protein as produced in the blood to prevent it from being active, with whatever its mechanism of action is. For antisense, this drug causes a missense reading of the messenger RNA to prevent the protein from being read out and made. It inhibits the protein being made itself and the drug has a special addition to it, which makes it liver specific, so it goes directly to the liver only because it can't go out other tissues. So, this is a new version, we had one that didn't have that. This one is 100-times more potent, so the dose is much lower. And we found that the drug could lower LDL, Lp(a) by about 80%.

 The results were quite remarkable, if you just look at raw numbers.

 Incredibly powerful. And now we're moving into so-called phase 3 trial, which hard endpoint is looking at reduction of cardiovascular events, and dose is going to be 80 mL once a month, compared to placebo. It'd be 50/50. We're talking about thousands of patients worldwide, it started already late last year, and COVID-19 has slowed down the process of it, as you would expect, but it's moving ahead. We're one of the sites and it looks in 5 years, hopefully, we'll be able to show that this drug not only lowers Lp(a), which we know it does, but lowers cardiovascular events on top of that. We have a paper coming out in 

JACC (Journal of the American College of Cardiology)

, giving an overview of the drug—its initiation, its progression—because we were working on this drug for a very long time. So, it gives you kind of an overview of the Lp(a) and of this drug itself. Now there's another drug that just finished its phase 1 trial and this is similar in the sense of inhibiting the messenger, but it's an RNA interference. This one has similar powerful effects, like the other one we just mentioned, but they're just initiating a phase 2 trial, so they're a little bit behind the competition.

: Well, at least there's competition, that's always good to know.

 It helps, your right. It speeds up the process and lowers hopefully the price.

 In general, in the world of preventive cardiology, is the idea of lowering Lp(a) well received? I know that the ACC/AHA and European counterpart both recommend using Lp(a) as a risk enhancer when looking at cardiovascular risk. Thirty percent of the population sounds like a big number, but does that mean we should be looking at Lp(a) in everyone, or just in these very specific patients?

 Well, I'm biased. I've been in this field for a long time but let me give you an idea. The American guidelines, as you said, recommends you measuring it as a risk enhancer only in patients who have cardiovascular disease, or very severe family history, because it doesn't change levels throughout your lifetime. The European guidelines came out last year and said, "We recommend universal testing for every adult at least once," which I think is the appropriate thing to do. Because it's not an expensive test, and there is ICD coding for it. So, it's a 1-time test and if it's normal, then for the rest of that person's life, they don't have to worry about it. But if it's elevated, then you have that risk enhancer, as you mentioned, on your medical history that should be identified.

: Again, I'm biased and I always say everyone should be and I think as time goes on, everyone will be. I don't know if you remember that TV show called The Biggest Loser. It was about an athletic guy who trained people who were overweight. A few years ago, he had a heart attack at age 50 and his heart attack was directly related to Lp(a). He had a massive MI in the gym. Luckily, there were 2 doctors in the gym that did CPR and he was in a coma for 2 days and woke up and found out his Lp(a) was high.

What's interesting—and I'll tell you this as a personal story—is that for strokes in children, unlike adults where 90% of strokes is related to thrombosis and atherosclerotic plaque, <2% of the strokes, thrombotic strokes in children, you find atherosclerosis at the source. And 40% of people <50 [years] when they have their stroke, thrombotic stroke not hemorrhagic, 40% is idiopathic. We just don't know why. We do know now that high Lp(a) in children increases their risk of a stroke. If they have a stroke with a high Lp(a) in the highest 90 percentile, they have a 10-fold risk of another stroke after their first one. I say that personally because I was sent a child from the children's hospital here in Kansas City, who had a stroke at age 11—thrombotic stroke, hemorrhagic, and obviously neurological deficits. They saw the thrombus and they brought him to KU to do, the invasive radiology team did a thrombectomy at the basilar artery. They removed the thrombus, but he still persisted with the symptoms. So, they consult, they did full bloodwork, hypercoagulable state. Nothing was there. His LDL was 60 milligrams per deciliter, but his Lp(a) was 160 where normal is <30. They consulted me and at that time I said the only thing we have at this point are my machines: the lipid apheresis machine, which is approved for treating Lp(a) now. We treated him and lowered his LDL and Lp(a) by 80%. He has been on this treatment now for 5 years, every 2 weeks, and he hasn't had an event. His neurological symptoms have greatly improved. Now, stroke in young children is very uncommon. The etiology is even more uncommon and that's where Lp(a) could be a major informative measure to do to see what's going on with these patients. And it's just a blood test, nothing complex.

conducted with Dr Moriarty, please go to 

Expert Update on Lp(a): Dr Patrick Moriarty Explains the Next CVD Target

Patrick Moriarty, MD, from the University of Kansas Medical Center, discusses the role of Lp(a) as a risk factor for cardiovascular disease and the phase 3 trials of a potential treatment.

Primary Viewpoints Episode 4: Lp(a): The Next CVD Target?

According to newly published data from the SPRINT study, 120 mm Hg may be the new normal blood pressure for a large group of people. But it’s hard enough getting most people to 140.

In this podcast, hypertension expert Dr. Daichi Shimbo provides a brief overview of that landmark study-and offers some tips about how you can help select patients achieve this new normal.

Dr. Shimbo is Associate Professor of Medicine, Columbia University; Director, Laboratory at the Center for Behavioral Cardiovascular Health; Director, Cardiovascular Physiology Research, Cardiovascular Ultrasound Laboratories; and Ewig Clinical Scholar at Columbia University Medical Center, New York, NY.

A randomized trial of intensive versus standard blood pressure control.

Podcast: Hypertension expert Daichi Shimbo, MD, offers tips on putting SPRINT results into clinical practice. 

120: The New Normal?

Will dipeptidyl peptidase-4 (DPP-4) antagonists find a secure position in the hierarchy of antidiabetes agents? Many signs point to “yes” for the fastest growing class of antihyperglycemic drugs: 
• Well tolerated
• Weight neutral
• Do not promote hypoglycemia
• Can be used in combination with traditional first-line agents
• Confer 0.5% to 1% additional reduction in A1C

Questions remain, however, about long-term safety of the DPP-4 inhibitors and their effects on cardiovascular outcomes, if any. In particular, an early signal for increased pancreatitis with some but not all members of this drug class, along with a small numeric excess of pancreatic cancer cases in some studies are now being systematically assessed for all  agents in the class. How should primary care physicians approach these agents and which patients might be candidates? 

In this short podcast, Dr Payal Kohli, host of Cardiology

 talks to Dr Darren McGuire about the DPP-4 antagonist class and the drugs’ benefits and risks as they are currently known. Dr Kohli is a cardiology fellow at the University of California San Francisco and Dr McGuire is Associate Professor of Medicine at UT Southwestern Medical Center, in Dallas; Associate of the Donald W. Reynolds Cardiovascular Clinical Research Center, and Director of the Parkland Hospital and Health System Outpatient Cardiology clinics. He is also senior editor of 

Take-home Points and Suggested Reading on next page...


•  Given their ease of administration, tolerability, and avoidance of weight gain and hypoglycemia, DPP-4 antagonists warrant consideration as second-line agents added to metformin, or even as first-line treatment for patients who cannot tolerate metformin or for who the drug is contraindicated. All antihyperglycemic agents should be prescribed against the backdrop of therapeutic lifestyle counseling as the cornerstone of treatment.
• The efficacy of glucose control is comparable to existing classes of oral antidiabetic agents, yielding approximately 0.5% to 1% additional HbA1c reduction either as monotherapy or added to existing drugs/drug combinations.
•  Meta-analyses thus far across this class of medications suggest approximately a 30% relative reduction in major adverse cardiovascular events, but these analyses are based on relatively few patients studied, few cardiovascular events captured, and relatively short duration of exposure. Cardiovascular outcomes trials are presently underway, with a total planned enrollment across the class of 50,000 trial participants.

There are several questions yet to be answered:
•  What, if any, increased risk for pancreatitis and/or pancreatic cancer is associated with DPP-4 antagonists?
•  If such risk exists, are there differential risks between the drugs in the class?
•  Finally, if these risks exist, how are they balanced by the DPP-4 antagonists’ efficacy against micro- and macrovascular disease complications?

These concerns are being addressed systematically in ongoing trial programs.




• Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. 

. 2012;344:e1369.
• Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. 

. 2010;20:224-235.
• Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. 

 2011;27 Suppl 3:s57-s64.
• Goossen K, Graber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. 

. 2012.
• Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. 

Dipeptidyl peptidase-4 inhibitors, of the incretin class of antidiabetes drugs, are weight neutral, avoid hypoglycemia, and result in an average reduction in HbA1c of 0.5% to 1.0%

DPP-4 Antagonists: Benefits, Risks, and the Future

The patient is a 55-year-old white man with no significant medical history. He has newly diagnosed hypertension: his blood pressure in your office is 152/94 mm Hg.

What agents will you consider for this patient?

Once upon a time, a beta-blocker might have been high on your list. When, if ever, should you consider prescribing these agents?

Here to debate the pros and cons of these agents are Gregory Rutecki, MD, Professor of Medicine at the University of South Alabama, and Bradley Wright, PharmD, at the Auburn University School of Pharmacy and the University of South Alabama.

Dr Rutecki focuses on the negative effects of beta-blockers; warns of the special risks of atenolol; and makes a case for consideration of carvedilol. Dr Wright zeroes in on the role of these agents in patients with a history of MI or congestive heart failure and discusses the possible mortality benefit from beta-blockers in patients with COPD.

Newly diagnosed hypertension in a patient whose blood pressure is 152/94 mm Hg. What agents will you consider for this patient? Beta-blockers? Think again.

The Great Beta-Blocker Debate: The Pros and Cons

LDL-cholesterol reductions of up to 85% were seen after the first week of therapy in the hardest-to-treat patients

-this remarkable finding related to experimental PCKS-9 inhibitors topped a roster of late-breaking clinical trial results at the American Heart Association’s 2012 Scientific Sessions, held in Los Angeles in early November. In this podcast, Dr Robert Giugliano, principal investigator of the LAPLACE-TIMI 57 trial, which studied PCSK-9 inhibition in patients with hypercholesterolemia, highlights his team’s results as well as findings from other key studies that are looking at the impact of anti-PCSK-9 monoclonal antibodies on LDL-cholesterol. The results are particularly promising in hard-to-treat populations, including patients unable to reach lipid goals on current statin therapy, patients who are statin-intolerant, and patients with genetic hypercholesterolemia. Cardiology

 host Dr Payal Kohli interviews Dr Giugliano, here.

Find additional details on studies discussed in this podcast, here:

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia: a randomised, placebo-controlled, dose-ranging, phase 2 study

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia: a randomised, double-blind, placebo-controlled, phase 2 study

PCSK-9 inhibitor to treat familial hypercholesterolemia

Reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder: results from a phase 2, randomized, double-blind, placebo-controlled trial.

PCSK-9 inhibitor in statin-intolerant patients

Goal achievement after utilizing an anti-PCSK9 antibody in statin intolerant subjects: interim results from a randomized, double-blind, placebo-controlled study

PCSK-9 inhibition in patients with recalcitrant hypercholesterolemia has reaped reductions in LDL-C of up to 85% after the first week of therapy.

Lipid-lowering Injectable Antibodies: The Next Big Thing?

• Multivitamins and omega-3s do not protect against heart disease.

• Coronary bypass is significantly more effective than percutaneous coronary intervention with drug-eluting stents for triple-vessel disease in patients with diabetes.

• The polypill enhances patient adherence to multidrug prevention strategies.

• Platelet function monitoring and adjustment of treatment based on results after coronary stenting does not improve clinical outcomes.

These findings made news among the late-breaking clinical trials presented at the American Heart Association’s 2012 Scientific Sessions in Los Angeles last week. These and other study results are also making headlines in the popular media and you may get questions from patients. Here, AHA Chair for the Committee on Scientific Sessions Dr Elliott Antman talks to Cardiology

 host Dr Payal Kohli about study results that may have direct impact on day-to-day primary care practice.


Additional study details are available here:

Strategies for multivessel revascularization in patients with diabetes

A randomized trial of bedside platelet function monitoring to adjust antiplatelet therapy vs Standard of care in patients undergoing drug eluting stent implantation

Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of a double-blind randomized clinical trial

A randomized trial of a multivitamin (MVM) in the prevention of cardiovascular disease in men

Use of a multidrug pill in reducing cardiovascular events

 host Dr Payal Kohli is a cardiology fellow at the University of California San Francisco, and Dr Antman is Professor of Medicine, Brigham and Women's Hospital, Senior Investigator, TIMI Study Group, and Associate Dean for Clinical/Translational Research at Harvard Medical School, all in Boston, Massachusetts.

Platelet function monitoring and adjustment of treatment based on results after coronary stenting does not improve clinical outcomes . . . and other findings from the AHA Scientific Sessions.

AHA 2012 Highlights: Multivitamins, Omega-3s, the Polypill, and More

What is a safe, effective, and inexpensive way to reduce the risk of heart attacks, strokes, and dementia? What we eat is a key part of the answer.

In this podcast, David T. Nash, MD, discusses the role of diet and exercise in cardiovascular disease prevention. Dr Nash is Clinical Professor of Medicine at Upstate Medical Center in Syracuse, New York. The author of more than 250 peer-reviewed clinical articles, Dr Nash has practiced cardiology in Syracuse for over 50 years. He is a Fellow of the National Lipid Association. Here, Dr Nash offers simple specific guidelines that may be helpful to your patient.


• Decrease saturated fat intake (ie, beef, full-fat cheeses, baked goods, palm oils)
• Add more soluble fiber to your diet (ie, with products containing psillium), including:

  • Bran Bud cereals, Kashi Go Lean (yellow box has 4 g per serving) (for every 1 g of soluble fiber you eat, you can reduce LDL levels by about 1%)
   • Fruits, including apple, oranges; beans; brown rice; guar gum; pectin
   • Plant stanol ester found in Benecol Margarine
   • Nuts, including almonds, pistachios, and walnuts
   • Soy products (eg, tofu)

The Protocol Diet From Dr Jenkins in Canada


This diet is appropriate for motivated patients, those who have had adverse reactions to drug therapy, and individuals who prefer a non-drug approach. One study showed that the Protocol Diet lowered LDL as much as a 20-mg dose of lovastatin.

1.2 g of plant sterols
8 g of soluble fiber
16 g almonds (1/2 oz)
16 g of soy protein

Other approaches to cardiovascular health


• Lower blood pressure with dark chocolate
• Use grapeseed oil to raise HDL levels (about 1 to 2 oz/d in salads, cooking, etc)


• Exercise daily, 30 to 60 minutes, to help lower high blood pressure and reduce lipid levels and obesity


• Foley DJ, White LR. Dietary intake of antioxidants and risk of Alzheimer disease: food for thought. 

 2002;287:3261-3263.
• Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. 

 2003;290:502-510.
• Milles EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. 

 2008;52:1769-1781.
• Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. 

 1990;336:129-133.
• Taubert D, Berkels R, Roesen R, Klaus W. Chocolate and blood pressure in elderly individuals with isolated systolic hypertension. 

What is a safe, effective, and inexpensive way to reduce the risk of heart attacks, strokes, and dementia? What we eat is a key part of the answer. For one thing, doctors can suggest an appropriate diet to motivated patients, or to those who prefer a non-drug approach.

Heart Attacks, Strokes, and Dementia: Reducing the Risk With Every Meal

The proposed beneficial role of omega-3 fatty acids in the reduction of cardiovascular (CV) events seemed to take a hit this summer when results of the 

 (n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia) were announced.

In patients with CV disease or who were at high risk for developing disease and who had dysglycemia or a diagnosis of type 2 diabetes, a combination of DHA and EPA 

 reduce triglyceride levels but failed to reduce the risk of death, the primary cardiovascular endpoint, or to reduce secondary ischemic endpoints.

Omega-3 fatty acids used to treat patients with dysglycemia in the ORIGIN trial failed to reduce cardiovascular death or ischemic events. Follow-up was 6 years.

Cardiovascular Disease

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