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

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 (ClinicalTrials.gov: 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.

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

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.

Primary Prevention of Cardiovascular Disease in Diabetes Mellitus.

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.

Diabetes mellitus is a coronary heart disease risk equivalent for peripheral vascular disease.

Diabetes mellitus (diabetes) is associated with significantly increased risk of peripheral vascular disease. Diabetes is classified as a coronary heart disease (CHD) risk equivalent, but it is unknown whether diabetes is a CHD risk equivalent for peripheral vascular disease. The objective was to evaluate the odds of peripheral arterial disease (PAD) or carotid artery stenosis (CAS) among participants with diabetes, CHD, or both, compared with participants without diabetes or CHD, in a nationwide vascular screening database. We hypothesized that diabetes and CHD would confer similar odds of PAD and CAS. METHODS: A cross-sectional analysis of all eligible Life Line Screening Inc participants age 30 to 90 years with ankle brachial indices for PAD (ankle brachial index <0.9 in either leg) and carotid artery duplex ultrasonographic imaging for CAS (internal CAS ≥50%) was performed (N=3,522,890). RESULTS: Diabetes and CHD were present in 372,330 (10.7%) and 182,760 (5.8%) of participants, respectively; PAD and CAS were present in 155,000 (4.4%) and 130,347 (3.7%) of participants. After multivariable adjustment, PAD odds were 1.56 (95% CI 1.54-1.59) and 1.69 (95% CI 1.65-1.73) for participants with diabetes or CHD, respectively. Participants with both diabetes and CHD had 2.75-fold increased odds of PAD (95% CI 2.66-2.85). Findings were similar for CAS; compared with no diabetes or CHD, CAS odds increased for participants with diabetes alone (1.53, 95% CI 1.50-1.56), CHD alone (1.72, 95% CI 1.68-1.76), and both diabetes and CHD (2.57, 95% CI 2.49-2.66). Findings were consistent for women and men. CONCLUSION: In a large database of more than 3.5 million self-referred participants, diabetes was a CHD risk equivalent for PAD and CAS, and participants with comorbid diabetes and CHD had an especially robust association with PAD and CAS. Counseling regarding screening and prevention of peripheral vascular disease may be useful for patients with diabetes.

Cardiovascular Effects of the New Weight Loss Agents.

The global obesity epidemic and its impact on cardiovascular outcomes is a topic of ongoing debate and investigation in the cardiology community. It is well known that obesity is associated with multiple cardiovascular risk factors. Although life-style changes are the first line of therapy, they are often insufficient in achieving weight loss goals. Liraglutide, naltrexone/bupropion, and phentermine/topiramate are new agents that have been recently approved to treat obesity, but their effects on cardiovascular risk factors and outcomes are not well described. This review summarizes data currently available for these novel agents regarding drug safety, effects on major cardiovascular risk factors, impact on cardiovascular outcomes, outcomes research that is currently in progress, and areas of uncertainty. Given the impact of obesity on cardiovascular health, there is a pressing clinical need to understand the effects of these agents beyond weight loss alone.

Management of Hypogonadism in Cardiovascular Patients: What Are the Implications of Testosterone Therapy on Cardiovascular Morbidity?

Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.

Overview of prescription omega-3 fatty acid products for hypertriglyceridemia.

Patients with elevated triglycerides (TG) may be at a higher risk for cardiovascular (CV) disease. Omega-3 fatty acids (OM3FAs), particularly the long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), effectively reduce TG and thus may impact CV outcomes; however, clinical data have been inconsistent. This review discusses the efficacy, safety, and key considerations of currently approved prescription OM3FA products in patients with elevated TG with or without concomitant elevations in other atherogenic parameters. Currently, 6 prescription OM3FA formulations are approved in the United States: omega-3-acid ethyl esters (Lovaza, Omtryg, and 2 generic formulations), omega-3-carboxylic acids (Epanova), which contain both EPA and DHA, and icosapent ethyl (Vascepa), which is an EPA-only formulation. All prescription OM3FA products effectively lower TG, with the magnitude of TG reduction affected by baseline TG level. Products that contain DHA can raise levels of low-density lipoprotein cholesterol, which is of particular concern in patients with atherosclerosis; Vascepa, however, does not raise these levels and therefore provides these patients with another option. Long-term outcomes trials for Vascepa (ongoing) and Epanova (planned) will help clarify the potential CV benefits in patients with persistent hypertriglyceridemia despite statin therapy.

Diabetes and vascular disease in different arterial territories.

OBJECTIVE: The aim of this study was to investigate the relationship between diabetes and different phenotypes of peripheral vascular disease (lower extremity peripheral artery disease [PAD], carotid artery stenosis [CAS], and abdominal aortic aneurysm [AAA]). RESEARCH DESIGN AND METHODS: Prevalence of vascular disease was evaluated in 3,696,778 participants of the Life Line Screening survey between 2003 and 2008. PAD was defined as ankle-brachial pressure index <0.90 or prior revascularization, CAS as ≥50% stenosis or prior revascularization, and AAA as infrarenal aortic diameter ≥3 cm or prior repair. Odds ratios (ORs) and 95% CIs were assessed using logistic regression modeling. RESULTS: Diabetes mellitus was present in 10.8% of participants (n = 399,884). Prevalence of PAD, CAS, and AAA was significantly higher (P < 0.0001) in participants with compared with those without diabetes. After multivariate adjustment for baseline demographics and clinical risk factors, a significant interaction existed between diabetes and vascular disease phenotype (P < 0.0001). Diabetes was associated with increased odds of PAD (OR 1.42 [95% CI 1.41-1.4]; P < 0.0001) and CAS (1.45 [1.43-1.47]; P < 0.0001) but decreased odds of AAA (0.86 [0.84-0.88]; P < 0.0001). The strength of association increased with increasing severity of disease in each vascular phenotype, and this association persisted in the population with asymptomatic vascular disease. CONCLUSIONS: In a large population-based study, the association between diabetes and vascular disease differed according to vascular phenotype. Future studies exploring the mechanism for these vascular-specific differences are needed.

Home and clinic blood pressure responses in elderly individuals with systolic hypertension.

Home blood pressure (BP) monitoring may enhance assessment of BP control. In this 16-week study, men and women 70 years or older with systolic BP between 150 and 200 mm Hg were randomized to receive valsartan/hydrochlorothiazide (V/HCTZ) 160/12.5 mg (n = 128), HCTZ 12.5 mg (n = 128), or V 160 mg (n = 128) for 4 weeks. Participants whose BP was 140/90 mm Hg or higher at weeks 4, 8, or 12 were uptitrated to a maximum of V/HCTZ 320/25 mg. Participants were evaluated by home BP monitoring using an automated device weekly before taking daily study medication (n = 301). Baseline BP ± SD for clinic (165.5 ± 11.8/85.1 ± 9.5 mm Hg) was approximately 3/1 mm Hg greater than home readings (162.5 ± 15.8/84.3 ± 10.2 mm Hg). Reductions in BP ± SEM at week 4 were similar for clinic (12.6 ± 1.0/4.7 ± 0.5 mm Hg) and home (10.9 ± 1.1/3.8 ± 0.5 mm Hg) readings (P = .25/P = .23; clinic versus home); differences between V/HCTZ and HCTZ or V were also similar for both home and clinic readings and results by either technique correlated significantly (P < .0001). Home BP measurements confirm that treatment initiated with V/HCTZ versus monotherapy resulted in greater antihypertensive efficacy. Home BP monitoring, if done with proper technique, provides a reliable indicator of BP control in elderly patients and may help guide drug dosing and titration.

Antihypertensive response to thiazide diuretic or angiotensin receptor blocker in elderly hypertensives is not influenced by pretreatment plasma renin activity.

PURPOSE: Renin profiling has been proposed as a method to guide antihypertensive drug selection. This prespecified post-hoc analysis examined the influence of baseline plasma renin activity (PRA) on blood pressure (BP) responses. METHODS: A 16-week, randomized, double-blind, prompted-titration trial evaluated initial valsartan (V)/hydrochlorothiazide (HCTZ) combination therapy versus initial HCTZ or V monotherapy in individuals aged ≥ 70 years with systolic hypertension. Sitting PRA was measured at baseline, Week 4, and Week 16. Subjects were stratified into 2 groups for analysis: low renin (baseline PRA < 0.65 ng/mL/h) or normal-high renin (baseline PRA ≥ 0.65 ng/mL/h). RESULTS: PRA data were available in 322/384 subjects: 178 had low PRA and 144 had normal-high PRA. At Week 4, V/HCTZ was more effective than HCTZ or V at reducing mean sitting systolic BP (MSSBP), independent of baseline PRA, with reductions of -16.9, -12.6, and -9.5 mmHg, respectively, in low-renin subjects and -19.4, -11.5, and -8.6 mmHg in normal-high renin subjects. Baseline PRA was similar in responders (subjects not uptitrated at Week 4) and nonresponders (subjects uptitrated at Week 4). In responders, the reactive rise in PRA at Week 4 was related to change in MSSBP, with the greatest increases in PRA observed in the V/HCTZ group. Higher baseline PRA was associated with a greater reactive rise in PRA. CONCLUSIONS: Baseline PRA is not a useful guide to the BP responses of initial combination V/HCTZ in elderly individuals with systolic hypertension.

The Role of Statin Therapy for Primary Prevention: What is the Evidence?

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of "intermediate-risk" patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.

Treating systolic hypertension in the very elderly with valsartan-hydrochlorothiazide vs. either monotherapy: ValVET primary results.

This 16-week trial investigated the efficacy and safety of single-pill valsartan/hydrochlorothiazide (HCTZ) vs. the individual components in patients 70 years and older with systolic hypertension. Patients were randomized to valsartan/HCTZ 160/12.5 mg (n=128), HCTZ 12.5 mg (n=128), or valsartan 160 mg (n=128) for 4 weeks. Patients whose blood pressure (BP) was ≥140/90 mm Hg at weeks 4, 8, or 12 were up-titrated to a maximum of valsartan/HCTZ 320/25 mg. Week 4 systolic BP reduction (primary efficacy outcome) was greater with valsartan/HCTZ than valsartan (-17.3 mm Hg vs. -8.6 mm Hg, P <.0001) but only marginally greater than HCTZ (-13.6 mm Hg, P =.096). Median time to BP control was shorter with valsartan/HCTZ (4 weeks) vs HCTZ (8 weeks, P<.05) or valsartan (12 weeks, P<.0001). Thiazide monotherapy was more effective than angiotensin receptor blocker monotherapy (by about 5 mm Hg), but greater antihypertensive efficacy was achieved by initiating treatment with combination valsartan/HCTZ in the elderly.

Effect of valsartan, hydrochlorothiazide, and their combination on 24-h ambulatory blood pressure response in elderly patients with systolic hypertension: a ValVET substudy.

BACKGROUND: Stage 2 hypertension often requires combination antihypertensive therapy. Ambulatory blood pressure monitoring (ABPM) is a useful tool for studying antihypertensive drugs and their combinations. OBJECTIVE: This multicenter, double-blind, parallel-group, prompted-titration study of patients of at least 70 years of age with systolic hypertension compared the efficacy of valsartan, hydrochlorothiazide, and their combination on ambulatory blood pressure (ABP) reduction. METHODS: After a 3-14-day washout, patients with systolic blood pressure of 150-200 mmHg were randomized (1 : 1 : 1) to initially receive once-daily valsartan/hydrochlorothiazide 160/12.5 mg combination therapy, hydrochlorothiazide 12.5 mg monotherapy, or valsartan 160 mg monotherapy. Prompted uptitration of patients in whom BP was more than or equal to 140/90 mmHg was performed after 4, 8, and 12 weeks of treatment. ABPM was performed at baseline and weeks 4 and 16 (study end). RESULTS: In this ABPM substudy (n=108), initiation of treatment with valsartan/hydrochlorothiazide lowered ABP more effectively than either monotherapy throughout the daytime, night-time, and 24-h monitoring periods, as well as during the last 4 and 6-h dosing periods. Twenty-four-hour ABP was reduced from 141.1/76.5 mmHg at baseline to 125.8/69.2 mmHg at week 4 (primary time point) with valsartan/hydrochlorothiazide compared with reductions from 142.2/78.7 to 139.1/77.5 mmHg with hydrochlorothiazide and 142.2/78.3 to 136.4/75.1 mmHg with valsartan (all P<0.01 in favor of combination therapy). In the overall study, tolerability was similar among the three treatment groups. CONCLUSION: In elderly hypertensives, starting combination therapy with valsartan/hydrochlorothiazide provides more effective 24-h blood pressure control than the monotherapy components, with few therapy-related side-effects.

Role of RAAS Inhibition in the Prevention of Cardiovascular Disease.

OPINION STATEMENT: The pathogenesis of cardiovascular disease is a complex and dynamic process. The renin-angiotensin-aldosterone system (RAAS) is a potent and powerful mediator in the homeostasis of the cardiovascular and renal systems. RAAS blockade via angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been consistently proven to be an effective and safe strategy for the primary and secondary prevention of cardiovascular disease in patients across a wide spectrum of risk. Although the beneficial effects of RAAS blockade may be due to its effects on central and peripheral blood pressure, there are many additional mechanisms to consider that may contribute additional protection. While a combination of ACE inhibitors and ARBs has not yielded significantly positive results, the newer class of direct renin inhibitors (DRIs) may offer a novel and effective strategy for monotherapy as well as in combination.

Potential benefits of aliskiren beyond blood pressure reduction.

There is now clear evidence that reducing blood pressure (BP) with a broad range of agents, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, improves cardiovascular and renal outcomes. There is also evidence suggesting that these drugs have beneficial effects that are independent of BP lowering. Aliskiren is a direct renin inhibitor that interrupts the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step. Unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aliskiren produces a sustained reduction in plasma renin activity and reduces plasma levels of angiotensin II and aldosterone. Preclinical data and clinical trials in high-risk patients using surrogate markers increasingly suggest that aliskiren can reduce the progression of end-organ damage beyond that afforded by BP control. With its unique mechanism of action, combining aliskiren with another RAAS-blocking agent that has a different mechanism of action may provide more comprehensive blockade of the RAAS, potentially conferring additional clinical benefits. Evaluation of these end-organ effects in humans is underway in clinical trials designed to assess the effects of aliskiren alone and in combination with other antihypertensive agents on cardiovascular and renal outcomes.

Combination therapy for managing difficult-to-treat patients with stage 2 hypertension: focus on valsartan-based combinations.

Blood pressure (BP) control rates in the United States remain low despite the availability of a wide array of treatment options. High-risk populations, including women, black individuals, and obese patients are even less likely to achieve BP targets than the general population. Uncontrolled BP can lead to serious consequences. Therefore, additional effective and well-tolerated treatment strategies are necessary, particularly for these difficult-to-treat populations. The majority of patients require 2 or more pharmacologic agents to achieve BP control. In patients with stage 2 hypertension, current guidelines recommend rational antihypertensive combinations as initial therapy. The renin-angiotensin-aldosterone system (RAAS) plays an important role in development of hypertension and progression, and the use of RAAS inhibitors has shown BP-lowering effectiveness and excellent tolerability across a continuum of patient types. Agents that block the RAAS form a reasonable foundation for combination therapy. In this article, we review data from studies of valsartan-based antihypertensive combinations in stage 2 hypertension, with a focus on women, black individuals, and obese patients.

Ranolazine: a new approach to treating an old problem.

Chronic angina pectoris affects millions of patients every year. During the past 2 decades, advances in medical therapy have led to substantial reductions in the symptoms of angina. Nonetheless, many patients continue to experience persistent angina that causes debilitating symptoms and lifestyle changes. Moreover, many current therapeutic agents cause side effects that can induce substantial morbidity on their own. In major clinical trials, the drug ranolazine has been shown to bring symptomatic relief to large numbers of patients who have chronic angina. Herein, we review the physiology of the sodium channel; the pharmacology of ranolazine; clinical trials that support use of the drug; recent evidence about ranolazine's therapeutic effect on diastolic heart failure, glycemic control, and atrial fibrillation and other arrhythmias; officially approved clinical indications; and avenues of future study.

Identifying the vulnerable patient with rupture-prone plaque.

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.