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Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a)

Koren, Michael J; Moriarty, Patrick Maurice; Baum, Seth J; Neutel, Joel; Hernandez-Illas, Martha; Weintraub, Howard S; Florio, Monica; Kassahun, Helina; Melquist, Stacey; Varrieur, Tracy; Haldar, Saptarsi M; Sohn, Winnie; Wang, Huei; Elliott-Davey, Mary; Rock, Brooke M; Pei, Tao; Homann, Oliver; Hellawell, Jennifer; Watts, Gerald F
Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran ( NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.
PMID: 35027752
ISSN: 1546-170x
CID: 5119102


Redel-Traub, G; Smilowitz, N; Weintraub, H; Schwartzbard, A; Berger, J
Background Mendelian randomization studies suggest that lifelong modest reductions of LDL cholesterol are associated with fewer major adverse cardiovascular events (MACE). We explored the relationship between the magnitude of LDL reduction from lipid lowering therapy, the duration of time over which LDL was reduced, and risk of MACE. Methods Randomized controlled trials of guideline-recommended LDL lowering therapy with >1000 participants and >2 year follow-up were systematically identified. Cross products of net LDL reduction and duration of follow-up were calculated. MACE was defined as the composite endpoint of cardiovascular death, acute coronary syndrome, revascularization, and stroke as available for each trial. Correlations were performed using the Pearson test. Results A total of 33 RCTs enrolling 249,887 participants with 50-month median follow-up were included. Trials tested statins (n=29), ezetimibe (n=2), and PCSK9 inhibitors (n=2). The cross product of LDL reduction and duration of therapy correlated with the relative risk reduction of MACE (r2=0.15; p=0.03). This association was most robust in secondary prevention trials (r2=0.44; p=0.0003). A significant correlation was not observed between LDL lowering and MACE without the dimension of time. Conclusion Our findings suggest that the intensity and duration of LDL lowering is most strongly correlated with MACE. These findings suggest potential benefit of early initiation of lipid lowering therapy in at risk patients. [Formula presented]
ISSN: 0735-1097
CID: 4884632

Migraine Patients With Cardiovascular Disease and Contraindications: An Analysis of Real-World Claims Data

Dodick, David W; Shewale, Anand S; Lipton, Richard B; Baum, Seth J; Marcus, Steven C; Silberstein, Stephen D; Pavlovic, Jelena M; Bennett, Nathan L; Young, William B; Viswanathan, Hema N; Doshi, Jalpa A; Weintraub, Howard
INTRODUCTION/UNASSIGNED:Triptans, the most commonly prescribed acute treatments for migraine attacks are, per FDA labeling, contraindicated in cardiovascular (CV) disease patients and have warnings and precautions for those with CV risk factors. METHODS/UNASSIGNED:Commercial Claims database was used to estimate the proportion of migraine patients with CV contraindications and warnings and precautions to triptans. RESULTS/UNASSIGNED:Of the 56,662 migraine patients analyzed from Optum CDM, 13.5% had ≥1 CV disease as specified in triptan labeling and an additional 8.5% had ≥1 "other CV disease" judged by the panel to constitute a "significant underlying CV disease" (total: 22.0% migraine patients). Of 176 724 migraine patients analyzed from MarketScan, 12.2% had ≥1 CV disease as specified in the labeling and an additional 8.0% had ≥1 "other significant underlying CV disease" (total: 20.2% of migraine patients). An additional 25.4% and 25.1% of migraine patients had ≥2 CV risk factors in Optum CDM and MarketScan. In total, 47.4% and 45.3% of migraine patients in both databases had a CV disease specified as a contraindication, an "other CV disease" endorsed as significant, or ≥2 CV risk factors identified as warnings and precautions to triptans. CONCLUSIONS/UNASSIGNED:Analyses of more than 230,000 people with migraine showed that ≥20% of commercially insured US migraine patients have a CV condition that specifically contraindicates triptan treatment, and an additional 25% have ≥2 CV risk factors identified as warnings and precautions to triptans.
PMID: 33095099
ISSN: 2150-1327
CID: 4652052

The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction: JACC State-of-the-Art Review

Newman, Jonathan D; Vani, Anish K; Aleman, Jose O; Weintraub, Howard S; Berger, Jeffrey S; Schwartzbard, Arthur Z
Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit. The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD as well as in diabetic patients with impaired renal function and heart failure.
PMID: 30286929
ISSN: 1558-3597
CID: 3329052

Biomarkers as Surrogates for Coronary Endothelial Dysfunction in Patients With Nonobstructive Coronary Artery Disease [Editorial]

Vani, Anish; Schwartzbard, Arthur; Weintraub, Howard S
PMID: 30371246
ISSN: 2047-9980
CID: 3400762

Investigation of Motivational Interviewing and Prevention Consults to Achieve Cardiovascular Targets (IMPACT) trial

Gianos, Eugenia; Schoenthaler, Antoinette; Guo, Yu; Zhong, Judy; Weintraub, Howard; Schwartzbard, Arthur; Underberg, James; Schloss, Michael; Newman, Jonathan D; Heffron, Sean; Fisher, Edward A; Berger, Jeffrey S
BACKGROUND:Patients undergoing cardiovascular (CV) procedures often have suboptimal CV risk factor control and may benefit from strategies targeting healthy lifestyle behaviors and education. Implementation of prevention strategies may be particularly effective at this point of heightened motivation. METHODS:A prospective, randomized, pilot study was conducted in 400 patients undergoing a nonurgent CV procedure (cardiac catheterization ± revascularization) to evaluate the impact of different prevention strategies. Patients were randomized in a 1:1:1 fashion to usual care (UC; group A, n = 134), in-hospital CV prevention consult (PC; group B, n = 130), or PC plus behavioral intervention program (telephone-based motivational interviewing and optional tailored text messages) (group C, n = 133). The primary end point was the Δ change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to 6 month. RESULTS:The mean age was 64.6 ± 10.8 years, 23.7% were female, and 31.5% were nonwhite. After 6 months, the absolute difference in non-HDL-C for all participants was -19.8 mg/dL (95% CI -24.1 to -15.6, P < .001). There were no between-group differences in the primary end point for the combined PC groups (B and C) versus UC, with a Δ adjusted between group difference of -5.5 mg/dL (95% CI -13.1 to 2.1, P = .16). Patients in the PC groups were more likely to be on high-intensity statins at 6 months (52.9% vs 38.1%, P = .01). After excluding participants with baseline non-HDL-C <100 mg/dL (initial exclusion criterion), Δ non-HDL-C and Δ low-density lipoprotein cholesterol were improved in the PC groups compared to UC (non-HDL-C -8.13 mg/dL [-16.00 to -0.27], P = .04; low-density lipoprotein cholesterol -7.87mg/dL [-15.10 to -0.64], P = .03). CONCLUSIONS:Although non-HDL-C reduction at 6 months following a nonurgent CV procedure was not significant in the overall cohort, an increased uptake in high-potency statins may translate into improved long-term health outcomes and cost reductions.
PMID: 29754664
ISSN: 1097-6744
CID: 3114632

The 2017 high blood pressure clinical practice guideline: The old and the new [Editorial]

Schwartzbard, Arthur Z; Newman, Jonathan D; Weintraub, Howard S; Baum, Seth J
PMID: 29574983
ISSN: 1932-8737
CID: 3011172

Primary Prevention of Cardiovascular Disease in Diabetes Mellitus

Newman, Jonathan D; Schwartzbard, Arthur Z; Weintraub, Howard S; Goldberg, Ira J; Berger, Jeffrey S
Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Yet, <50% of U.S. adults with T2D meet recommended guidelines for CVD prevention. The burden of T2D is increasing: by 2050, approximately 1 in 3 U.S. individuals may have T2D, and patients with T2D will comprise an increasingly large proportion of the CVD population. The authors believe it is imperative that we expand the use of therapies proven to reduce CVD risk in patients with T2D. The authors summarize evidence and guidelines for lifestyle (exercise, nutrition, and weight management) and CVD risk factor (blood pressure, cholesterol and blood lipids, glycemic control, and the use of aspirin) management for the prevention of CVD among patients with T2D. The authors believe appropriate lifestyle and CVD risk factor management has the potential to significantly reduce the burden of CVD among patients with T2D.
PMID: 28797359
ISSN: 1558-3597
CID: 2664152

Cardiovascular disease leads to a new algorithm for diabetes treatment

Rodriguez, Valentina; Weiss, Matthew C; Weintraub, Howard; Goldberg, Ira J; Schwartzbard, Arthur
Patients with diabetes mellitus have increased rates of atherosclerotic cardiovascular disease (CVD) and heart failure (HF). This increase occurs despite optimal lipid-lowering therapies. We reviewed clinical trials of diabetes treatments and their effects on circulating plasma lipoproteins and CVD. Several earlier studies failed to demonstrate clear CVD benefit from diabetes therapies. In addition, triglyceride-reducing agents did not reduce overall CVD in large clinical trials although these trials were not conducted in cohorts selected as hypertriglyceridemic. Specific classes such as the thiazolidinediones increased HF. After Food and Drug Administration mandates for more rigorous safety data, recent studies have not only demonstrated CVD safety for many diabetes mellitus agents, but have also shown that certain newer medications such as empagliflozin, canagliflozin, liraglutide, and semaglutide reduce CVD. Moreover, pioglitazone use in insulin-resistant patients has resulted in decreased cerebrovascular and cardiovascular events, suggesting a protective vascular effect of this agent. Benefits from these newer classes of medications are unlikely to be because of improved lipoprotein profiles. These disparities in diabetes medication effects on CVD are likely attributable to each drug or drug class' cardiometabolic effects. Selecting medications based solely on their potential to lower hemoglobin A1C is an outdated therapeutic approach. We propose a new algorithm for treatment of patients with type II diabetes such that medication selection is based on the presence or risk of coronary artery disease and/or HF.
PMID: 28822714
ISSN: 1933-2874
CID: 2676772

Lipoprotein(a) screening in patients with controlled traditional risk factors undergoing percutaneous coronary intervention

Weiss, Matthew C; Berger, Jeffrey S; Gianos, Eugenia; Fisher, Edward; Schwartzbard, Arthur; Underberg, James; Weintraub, Howard
BACKGROUND: Lipoprotein(a) [Lp(a)] is an inherited atherogenic lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease; however, its clinical role remains limited. OBJECTIVE: We hypothesized that Lp(a) screening in high cardiovascular risk patients could provide insight into disease pathogenesis and modify physician behavior for treatment intensification targeting traditional risk factors when Lp(a)-related risk was identified. METHODS: We screened 113 patients presenting electively for percutaneous coronary intervention (PCI) for Lp(a) who met any of the following criteria: (1) premature coronary artery disease (male age <55 years, female age <65 years); (2) family history of premature coronary artery disease; (3) progression to PCI despite well-controlled traditional risk factors (blood pressure <140/90 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL, and HbA1c <7%, and nonsmoker); or (4) progression to PCI despite at least moderate intensity statin use (simvastatin 40, atorvastatin 40-80, or rosuvastatin 20-40 mg daily). RESULTS: In this high-risk cohort, Lp(a) was elevated in nearly half of all subjects, including those with seemingly well-controlled lipids by prior guidelines, suggesting a role for Lp(a) in conferring residual cardiovascular risk. In our cohort, when screened positive, knowledge of an elevated Lp(a) did not influence referring physicians' treatment intensification targeting traditional modifiable cardiovascular risk factors (P = .18). CONCLUSION: When screened judiciously, elevated levels of Lp(a) are highly prevalent in high cardiovascular risk patients, including at a young age, presenting for PCI and may contribute to previously unappreciated residual cardiovascular risk.
PMID: 28801030
ISSN: 1933-2874
CID: 2664272