Different targets available for preventing CVD in cardiometabolic conditions
LAS VEGAS — Data suggest that numerous medications have the ability to reduce LDL and the risk for CVD in patients with cardiometabolic conditions, although deciding which treatment is best suited for a patient may need to be done on a case-by-case basis, according to a presentation at National Lipid Association Scientific Sessions.
Evolving approach to prevention
In the 1980s, the most common CV risk factors in young patients were heavy smoking and high cholesterol, and premature MI was seen more in patients who had obesity and diabetes or were women. Although some progress has been made, the latest data show that the age-adjusted rate of CVD death has increased for the first time in decades. This may be attributed to an epidemic of diabetes and an increase in obesity.
“[What’s] even more worrisome is what’s happening with young people,” Christie M. Ballantyne, MD, professor of medicine, chief of the sections of cardiology and cardiovascular research and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, said in the presentation.
More adolescents are being diagnosed with type 2 diabetes, which can pose a threat 2 or 3 decades later.
Information on patients who are having MIs at younger ages has led to greater understanding of adipose tissue biology, Ballantyne said. The focus is moving beyond intramyocellular fat and into perimyocellular fat, which is inflammatory and may have an impact on insulin resistance.
“This challenge is offsetting a lot of our advances,” Ballantyne said. “It’s going to take a comprehensive approach of diet and lifestyle and pharmacotherapy.”
Benefits of ezetimibe
Ezetimibe prevents the absorption of cholesterol, which leads to LDL reductions and the increased LDL clearance receptors, which further contributes to LDL lowering. When treating patients with cardiometabolic conditions or even patients in general, it is important to consider the long-term benefits of a drug like ezetimibe, Joseph J. Saseen, PharmD, CLS, FNLA, professor and vice chair of the department of clinical pharmacy and professor in the department of family medicine at University of Colorado Anschutz Medical Center in Aurora, said in the presentation.
Ezetimibe has an interesting history dating back to 2002, when it was first approved, Saseen said. In the SEAS trial, it was found that ezetimibe may increase the risk for cancer, which was then determined to be unlikely by the FDA.
As previously reported by Cardiology Today, the IMPROVE-IT trial found that the addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with ACS compared with simvastatin alone.
“It had a real difference, but a lot of clinicians struggled with the clinical relevance of this small reduction in cardiovascular events,” Saseen said.
In the Cholesterol Treatment Trialists meta-analyses, these results fell along the same LDL reduction/CV reduction benefit regression line that has historically been demonstrated with statins, which implies that the benefit was potentially from LDL reduction, Saseen said. In an analysis of IMPROVE-IT comparing patients with and without diabetes, the benefit of ezetimibe to reduce CV events was driven by patients with diabetes (P for interaction = .023).
There were also no differences in safety profiles in patients with and without diabetes, even in the subgroups with lower LDL values in patients with diabetes.
“Overall, safety-wise, we should have a good comfort level in using ezetimibe long-term,” Saseen said.
The FOURIER trial assessed the benefits of the PCSK9 inhibitor evolocumab (Repatha, Amgen). Cardiology Today previously reported that the reduction of LDL to a median of 30 mg/dL with evolocumab in patients with atherosclerotic CVD was associated with reduced risk for CV events.
“It can take some time for patients who are stable and are treated with a PCSK9 inhibitor to see a benefit,” Robert P. Giugliano, MD, SM, senior investigator in the TIMI Study Group, cardiovascular medicine physician at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said in a presentation.
“You don’t expect that after 60-some years of bad habits, for example, a poor diet, inactivity and smoking, in a patient with a high LDL that you give a PCSK9 inhibitor and tomorrow you prevent MIs,” Giugliano said. “In fact, it takes 6 to 9 months.”
Robert P. Giugliano, MD, SM, senior investigator in the TIMI Study Group, cardiovascular medicine physician at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said in a presentation.
“You don’t expect that after 60-some years of bad habits, high LDL and smoking that you give a PCSK9 inhibitor and tomorrow you prevent MIs,” Giugliano said. “In fact, it takes 6 to 9 months.”
In FOURIER, there were no differences in patients with and without diabetes for the treatment effect of evolocumab for prevention of major adverse CV events (P for interaction = .6). In addition, he said, assignment to evolocumab or placebo did not impact HbA1c or fasting plasma glucose levels.
The GLAGOV trial, as previously reported by Cardiology Today, provided insight into LDL reduction with a PCSK9 inhibitor in patients with diabetes, as patients with CAD who had evolocumab added to their statin regimen experienced greater reductions in plaque metrics and LDL than those who had placebo added to their regimen.
In FOURIER, when categorizing patients by LDL levels at 4 weeks, efficacy was associated with a further lowering of LDL, and this benefit was weakened when higher LDLs were achieved. The greatest benefit was seen in patients who achieved very low LDL. There was no difference in safety in all groups, Giugliano said.
SGLT2 inhibitors and GLP-1 agonists
Although CAD and stroke are common in patients with diabetes, congestive HF is also prevalent in this patient population, which was largely shown through the Framingham study, Valentina Rodriguez, MD, clinical instructor and faculty in the division of endocrinology, diabetes and metabolism at NYU Langone Health, said in the presentation.
Glucagon-like peptide-1 (GLP-1) is an incretin that is secreted by the gut, which is stimulated by food intake. It can have a variety of effects on areas such as the pancreas, beta cells and alpha cells.
In the LEADER trial, patients with type 2 diabetes and a history of CVD assigned liraglutide (Victoza, Novo Nordisk) therapy saw reduced risk for CV death, nonfatal MI and stroke vs. those assigned a placebo. Although not statistically significant, hospitalization for HF was also reduced in patients using liraglutide, suggesting it may have a HF benefit as well, although this has not been the case with patients with advanced HF, as seen in the FIGHT trial.
Semaglutide (Ozempic, Novo Nordisk), another GLP-1 agonist, reduced risk for major adverse CV events in a similar patient population in the SUSTAIN-6 trial.
“Interestingly, what really led to the benefit was the reduction of stroke in these patients,” Rodriguez said.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors target the nephron in the kidneys.
“This is really exciting because before this class of medication, no other diabetes medications really targeted the kidneys,” Rodriguez said.
As previously reported by Cardiology Today, the EMPA-REG OUTCOME study found that empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly), an SGLT2 inhibitor, is associated with decreased risk for HF hospitalization or CV death and other HF-related endpoints.
“Unlike the PCSK9 inhibitors, where we have to wait several months for a benefit to happen, this benefit … starts to occur within a few weeks,” Rodriguez said. “Though we are not sure of the mechanism or why this is happening, it’s definitely significant when we’re considering treatment.”
In the CANVAS trial, canagliflozin (Invokana, Janssen) confirmed the CV benefit of SGLT2 inhibitors by significant reductions in CV death, nonfatal MI and nonfatal stroke.
Rodriguez and colleagues at NYU developed a new algorithm to determine whether an SGLT2 inhibitor or a GLP-1 agonist would be best suited for a patient with diabetes already taking metformin. She said the choice is dependent on whether they have conditions such as CHD, atherosclerotic CVD, HF, stroke and CAD.
DAPT and anticoagulation
The pathophysiology of ACS involves the interaction between atherogenic lipids, platelets and inflammation, Pam R. Taub, MD, director of Step Family Cardiac Wellness and Rehabilitation Center and associate professor of medicine at University of California, San Diego Health in La Jolla, said in the presentation.
The role of inflammation in these patients is starting to emerge because more has become known about the role of certain cells of the immune system such as macrophages in converting a stable plaque to an unstable plaque, she said. The thrombus is the final common pathway in ACS, which is treated with antithrombotic and antiplatelet therapy in the acute setting, yet in the chronic management of stable atherosclerotic CVD, we are not as aggressive with DAPT.
“Lipidologists should care about platelets because when you look at it from a mechanistic standpoint, elevated lipids actually cause platelet activation and biogenesis,” Taub said.
One of the key components of the coagulation pathway is factor Xa and its inhibition. Its inhibition leads to a decrease in both fibrin and thrombin, which is the most potent platelet activator, Taub said.
The only pathway of aspirin is COX-1. Though its inhibition is important, it can be overcome as platelets have multiple receptors that can lead to their activation, according to the presentation. Other pathways that can be targeted in addition to COX-1 are P2Y12 and PAR-1 receptors.
“This is where the concept of dual antiplatelet therapy is important because just hitting one pathway such as COX-1 is not going to be sufficient, especially in a diabetic who’s extremely hypercoagulable,” Taub said.
Compared with aspirin alone, data have shown that DAPT is beneficial for this patient population.
Current guidelines do not fully explain how to treat patients at high risk for ACS and other events, and the only guidelines available focus on patients 1 year after PCI, she said.
In the DAPT trial, researchers assessed the continuation of DAPT for a longer period of time. It found that this therapy is reasonable, but health care providers should weigh it against bleeding consequences.
The available DAPT score can be used to determine the best treatment for this patient population, but it often underestimates risk in patients with diabetes because it does not factor in A1c and early aggressive coronary disease or polyvascular disease, which is associated with increased thrombus burden, Taub said.
In the COMPASS trial, researchers analyzed the effects of a non-vitamin K antagonist oral anticoagulant in patients with CAD and/or PAD who were assigned rivaroxaban (Xarelto, Janssen) with or without aspirin vs. aspirin alone. Those assigned low-dose rivaroxaban (2.5 mg twice per day) with aspirin had the greatest net benefit compared with other groups. This group also had the lowest clinical event rate.
“In summary, platelets are underappreciated, but are an important therapeutic target in the management of the complex cardiometabolic patient,” Taub said.
C-reactive protein as a marker of residual inflammatory risk was seen in numerous statin trials, Peter H. Jones, MD, FNLA, associate professor at Methodist DeBakey Heart and Vascular Center, Baylor College of Medicine, said in the presentation. Trials such as PROVE-IT and IMPROVE-IT found that lower CRP and LDL conferred best outcomes in trials involving patients on statin therapy.
Interleukin-1 beta and interleukin-6 directly affect the arterial wall, which results in an increase in plaque growth and a decrease in vascular function, according to the presentation. Blocking interleukin-1 beta may affect endothelial cell function and reduce the production of cytokines.
In the CANTOS trial, as previously reported by Cardiology Today, canakinumab (Ilaris, Novartis) in combination with standard-of care therapy reduced the risk for major adverse CV events in patients with prior MI and inflammatory atherosclerosis. Risk reduction was dependent on the response to CRP.
“The benefits of CRP reduction, cardiovascular morbidity and all-cause mortality are very intriguing,” Jones said. “We haven’t seen that with just lipid reduction alone, particularly in the group that responded to canakinumab early with a robust in [high-sensitivity] CRP.”
Although incidence was low, patients with canakinumab had an increased risk for leukopenia and more serious infections. These patients also had improvements in arthritis, fatal malignancy and gout.
“We should lower LDL a lot and lower inflammation a lot, and if we do, we would have the best absolute risk reduction, particularly in the patient with premature coronary disease,” Jones said. – by Darlene Dobkowski
Taub PR. NLA Special Opening Session: Expert Debate on CVD Risk Reduction in the Cardiometabolic Patient. All presented at: National Lipid Association Scientific Sessions; April 26-29, 2018; Las Vegas.
Ballantyne reports he receives grant/research support from Abbott Diagnostics, Amarin, Amgen, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostics and Sanofi Synthelabo and consults for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostics and Sanofi Synthelabo. Giugliano reports he received grants from Amgen and Merck, honoraria for CME programs from Amgen and Merck and consultant/advisory board for Amarin, American College of Cardiology, Amgen, CVS Caremark, Lexicon and Merck. Rodriguez and Saseen report no relevant financial disclosures. Taub reports she received research grants from Amgen and is a consultant/advisory board member for Amgen, Aralez, Boehringer Ingelheim, Janssen and Regeneron.