Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons.

AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition. BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality. However, 70% of events occur even in the presence of statins. This residual risk may be approached with additional LDL-C reduction. Statin intolerance is a common clinical concern affecting adherence and the benefit with statins. There is also significant variation of individual lipid-lowering. Following rapid development, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have progressed from genetic observations, to mechanistic studies, to closer realization of the goal of CVD risk reduction. This review discusses the science behind PCSK9 inhibition, evidence of trials involving efficacy and safety, and reflections of its present and future role in clinical care, especially in high-risk patients with ASCVD, persons with suboptimal responses to statins and familial hyperlipidemia. Monoclonal antibodies have demonstrated LDL-C lowering of up to 57% as monotherapy and up to 73% when added to statins. Statins have limited efficacy in reduction of LDL-C due to an increased number of LDL-receptors. Elevated lipoprotein (a) levels may also be significantly lowered by PCSK9i. The journey from discovery to PSCK9 target validation took less than five years, and development and approval of therapeutic modalities for PCSK9 inhibitors happened over the next seven. This review highlights the drug development and pharmacogenomics leading to the recent approval of two agents, alirocumab and evolocumab, with a third bococizumab, and other novel approaches to the pathway pending. DATA SYNTHESIS: We searched MEDLINE database via Pubmed for reviews, research publications and relevant trials available on PCSK9 inhibition. CONCLUSION: Despite decades of medical advances, ASCVD remains one of the major causes of morbidity and mortality worldwide. Statin use has multiplied since the validation of LDL hypothesis, however, it is undeniable a more effective and well-tolerated agent is needed in significant number or patients. With the arrival of the era of unprecedented CV protection with PCSK9 inhibition, this exciting new therapy holds a pivotal promise as the future of lipid management. The data available already indicate safety, tolerability and superb efficacy of these agents, which are already changing contemporary cholesterol management. The rapid translation of innovative basic science research into drug development may lead to CV outcomes reduction and confirm that this pathway will become prominently utilized.

Effects of nebivolol in obese African Americans with hypertension (NOAAH): markers of inflammation and obesity in response to exercise-induced stress.

We sought to determine whether the antihypertensive drug nebivolol has beneficial effects on vascular markers of inflammation and oxidation in obese African-American patients with hypertension when exposed to exercise-induced stress. Forty-three obese, African-American subjects with hypertension were treated with nebivolol (5-10 mg/day) for 8 weeks. Before treatment the subjects underwent an exercise treadmill study to a level of eight metabolic equivalents. Circulating levels of soluble interleukin-6 (sIL-6), vascular cell adhesion molecule (VCAM-1), adiponectin and leptin were measured at pre-treadmill, and 1 min, 30 min, 60 min and 24 h after treadmill. After the 8-week treatment period, exercise treadmill study and the measurement of markers were repeated. Treatment with nebivolol reduced levels of sVCAM-1 at pre-exercise by 21% and at 1 and 30 min by 12.5 and 20%, respectively (P<0.005 from corresponding time point). In nebivolol-treated patients there was a reduction in sIL-6 levels by 20% and pre-exercise and at 1 and 60 min by 19.7 and 33.5%, respectively (P<0.005 from corresponding time point). Treatment with nebivolol increased levels of serum adiponectin by 28% (P=0.012) and decreased levels of leptin by 32% (P<0.005 from pre-treatment). Treatment with nebivolol improves markers of inflammation and obesity in a high-risk African-American population. Moreover, this effect is potentiated in response to exercise-induced stress. These results suggest that nebivolol differentially regulates markers of inflammation and obesity, thereby providing vascular protection.

Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor.

The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. Omapatrilat, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8.

Update in pharmacologic treatment of hypertension.

Initial pharmacologic therapy for hypertension is low-dose thiazide diuretics, beta-blockers, and ACE inhibitors. Increasing data have confirmed that ACE inhibitors have specific benefit in patients with diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency. CCBs are alternative agents for ISH in the elderly and appear to decrease stroke with perhaps less protection against progression of renal insufficiency and proteinuria, CAD mortality and new onset heart failure versus other initial agents, especially ACE inhibitors. ARBs are well tolerated and effective blood pressure lowering agents but have not been confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure. Effective pharmacologic antihypertensive therapy may avoid disabling and undetected cerebrovascular disease, cognitive dysfunction, and disturbing symptoms of elevated blood pressure. Vasopeptidase inhibitor, such as omapatrilat, and endothelin-1 antagonist, such as bosentan, may become future agents approved for the reduction of morbidity and mortality with hypertension. The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in a diverse high-risk population. Based on ALLHAT data, however, doxazosin is no longer an acceptable initial pharmacological agent. Intensive pharmacologic treatment with blood pressure lowering to less than 130/85 mm Hg is recommended with diabetes, renal insufficiency, and heart failure with additional goal of less than 125/75 mm Hg with renal failure and proteinuria greater than 1 g/24 h, based on multiple outcome studies.

Coronary heart disease in African Americans.

African Americans have the highest overall mortality rate from coronary heart disease (CHD) of any ethnic group in the United States, particularly out-of-hospital deaths, and especially at younger ages. Although all of the reasons for the excess CHD mortality among African Americans have not been elucidated, it is clear that there is a high prevalence of certain coronary risk factors, delay in the recognition and treatment of high-risk individuals, and limited access to cardiovascular care. The clinical spectrum of acute and chronic CHD in African Americans is similar to that in whites. However, African Americans have a higher risk of sudden cardiac death and present more often with unstable angina and non-Q-wave myocardial infarction than whites. African Americans have less obstructive coronary artery disease on angiography, but may have a similar or greater total burden of coronary atherosclerosis. Ethnic differences in the clinical manifestations of CHD may be explained largely by the inherent heterogeneity of the coronary syndromes, and the disproportionately high prevalence and severity of hypertension and type 2 diabetes in African Americans. Identification of high-risk individuals for vigorous risk factor modification-especially control of hypertension, regression of left ventricular hypertrophy, control of diabetes, treatment of dyslipidemia, and smoking cessation--is key for successful risk reduction.

Hypertension: how comorbid disease influences the choice of therapy. Part 4 of a roundtable discussion.

Two categories of comorbid conditions affect the choice of therapy for hypertension: compelling indications, where outcomes data show improved survival, and indications where therapies may be beneficial but do not affect survival. In patients with diabetes, low-dose diuretics effectively lower blood pressure, but metabolic derangements may occur. A diuretic may exacerbate urinary incontinence and therefore may not be a first-choice therapy for some older women. Monotherapy is not effective in controlling blood pressures in patients with renal insufficiency. In patients with a history of MI, even those age 85 and older benefit from beta blockade. Lowering blood pressure over a 3- to 5-year period is effective in preventing left ventricular hypertrophy and congestive heart failure.

Hypertension: therapeutic approach to weight loss, exercise, and salt intake.

Ideal body weight is difficult to achieve, but losing 10 lbs may be beneficial in controlling high blood pressure. Patients are more likely to exercise if they enjoy the activity, establish a routine, and exercise with a friend. Older Americans consume a lot of processed foods, the source of 80% of dietary salt. Most older African-Americans, especially those with obesity and type 2 diabetes, are salt-sensitive. Four steps to successful patient education are: 1) tell patients their blood pressure readings; 2) tell them about their medications and potential side effects; 3) provide culturally-sensitive printed materials; 4) use video tapes to educate all new patients and those with compliance problems.

Hypertension: setting new goals for lower readings.

Mean systolic blood pressures increase and mean diastolic pressures decrease with aging, primarily in response to the stiffening of blood vessels. These trends are related to the interplay of genetic factors that control renal, vascular, and hormonal functions. The prevalence of hypertension and the rate of blood pressure control vary among population groups; only one-fourth (24%) of all Americans with hypertension are controlled. Some persistent myths about hypertension may interfere with its diagnosis and treatment. Other barriers to control appear to be the side effects and cost of medications. Control rates improve when physicians increase their emphasis on patient education.

Lessons learned from the Healthy Heart Community Prevention Project in reaching the African American population.

The Healthy Heart Community Prevention Project (HHCPP) is an ongoing program of cardiovascular risk identification and modification in the African American community in New Orleans, Louisiana. The program targets low socioeconomic status African American populations, which continue to have higher rates of coronary heart disease, stroke, and overall cardiovascular mortality than the general population. Among the HHCPP's initiatives have been the use of barbershops and beauty salons as blood pressure screening sites. Church-based programs, in which ministers provide "healthy heart sermons," as well as screenings at sports events, where volunteers provide health advice, have proven to be successful aspects of the program. The HHCPP has also offered educational sessions to a broad cross-section of health professionals, including physicians as well as nurse practitioners and nutritionists. Future initiatives include the establishment of cholesterol screening programs.

The physician's role in minimizing prehospital delay in patients at high risk for acute myocardial infarction: recommendations from the National Heart Attack Alert Program. Working Group on Educational Strategies To Prevent Prehospital Delay in Patients at High Risk for Acute Myocardial Infarction.

Physicians and other health care professionals play an important role in reducing the delay to treatment in patients who have an evolving acute myocardial infarction. A multidisciplinary working group has been convened by the National Heart Attack Alert Program (which is coordinated by the National Heart, Lung, and Blood Institute of the National Institutes of Health) to address this concern. The working group's recommendations target specific groups of patients: those who are known to have coronary heart disease, atherosclerotic disease of the aorta or peripheral arteries, or cerebrovascular disease. The risk for acute myocardial infarction or death in such patients is five to seven times greater than that in the general population. The working group recommends that these high-risk patients be clearly informed about symptoms that they might have during a coronary occlusion, steps that they should take, the importance of contacting emergency medical services, the need to report to an appropriate facility quickly, treatment options that are available if they present early, and rewards of early treatment in terms of improved quality of life. These instructions should be reviewed frequently and reinforced with appropriate written material, and patients should be encouraged to have a plan and to rehearse it periodically. Because of the important role of the bystander in increasing or decreasing delay to treatment, family members and significant others should be included in all instruction. Finally, physicians' offices and clinics should devise systems to quickly assess patients who telephone or present with symptoms of a possible acute myocardial infarction.

Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension.

A factorial design was applied in this multicenter, double-blind, placebo-controlled trial of the calcium-channel blocker verapamil and the ACE inhibitor enalapril to assess the hypotensive effects of the combination compared with monotherapy, to evaluate safety, and to determine the effects on quality of life (QOL) of both drugs, alone and in combination. The study consisted of a 3 x 2 factorial design wherein 186 men and women with a sitting diastolic blood pressure (BP) of between 95 mm Hg and 114 mm Hg, after a 4-week placebo washout, were randomized to one of six treatment groups for 4 weeks of active treatment. Monotherapy with both 240 mg verapamil and 10 mg enalapril reduced systolic and diastolic BP to a similar extent and significantly more than placebo. The 240 mg verapamil + 10 mg enalapril combination was additive for both systolic and diastolic blood pressure; 120 mg verapamil + 10 mg enalapril was additive for systolic BP only. The total number of adverse events reported was similar for all six treatment groups. QOL scores were unchanged from baseline and not different between treatment groups. The combination of 240 mg verapamil and 10 mg enalapril was significantly more effective at reducing BP than either drug alone; this additivity of effect was not linked to a higher rate of adverse experiences or to a deterioration in QOL. Thus, combination therapy at lower doses may offer an alternative treatment option to higher dose monotherapy.

Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil.

The efficacy and safety of a low dose (120 mg) of a sustained-release capsule formulation of verapamil administered once daily in the treatment of 42 patients with mild hypertension were assessed in this clinical trial. After a 4-week placebo washout period (baseline), patients with diastolic clinic blood pressures of 91 to 100 mm Hg inclusive were treated for 4 weeks with once-daily verapamil sustained-release 120 mg capsules. Clinic blood pressure was measured and 24-hour ambulatory blood pressure monitoring was performed at the end of both the baseline and the 4-week treatment periods. Twenty-four hour, day, and night systolic and diastolic ambulatory blood pressure were significantly (P < 0.01) reduced in the entire study population (24-hour, -5/-4 mm Hg; day, -6/-4 mm Hg; night, -4/-3 mm Hg). On the basis of mean daytime (6 AM to 6 PM) ambulatory diastolic blood pressure, patients were stratified into subgroups of patients with confirmed (> 85 mm Hg) and unconfirmed mild hypertension (< or = 85 mm Hg). The magnitude of the mean change in systolic and diastolic blood pressure was greater in the group of patients with confirmed mild hypertension than the group with unconfirmed hypertension. The incidence of adverse experiences was low in frequency and events were of mild severity; quality of life scores improved (P = 0.02). Low daily doses (120 mg) of verapamil sustained-release capsules provide a well-tolerated and sustained antihypertensive effect over 24 hours in patients with mild hypertension.

Comparison of the efficacy and metabolic effects of nicardipine and hydrochlorothiazide in hypertensive black men and women.

A double-blind, randomised, parallel study compared the BP and metabolic responses in black hypertensive patients following monotherapy with nicardipine or hydrochlorothiazide (HCTZ). Following a single-blind placebo wash-out period of 1-4 weeks, the study drug, nicardipine 20-40 mg three times daily or HCTZ 25-100 mg four times daily, was administered in a double-blind fashion for 12 weeks. Doses were titrated to control sitting DBP (< or = 90 mmHg). Both drugs were effective in reducing sitting SBP and DBP as compared with baseline values (nicardipine: 152.5 +/- 1.6/102.0 +/- 0.6, HCTZ: 152.5 +/- 1.5/101.4 +/- 0.5 mmHg). DBP responses (reduction from baseline; nicardipine: -10.9, HCTZ: -12.7 mmHg), and the percentage of patients achieving a response < or = 90 mmHg (nicardipine: 54%, HCTZ: 63%) to the two drugs were similar. Although SBPs at baseline and endpoint (137.3 +/- 1.6 on nicardipine and 132.1 +/- 1.4 mmHg on HCTZ), and the percentage of patients achieving a response < or = 140 mmHg (nicardipine: 70%, HCTZ: 79%), were comparable between the two treatments, the SBP reduction with HCTZ was statistically greater (P = 0.026). A comparison of the metabolic responses in the two treatment groups showed significant differences. Nicardipine caused no significant changes in blood chemistry, whereas HCTZ caused statistically significant decreases (P < 0.001) in sodium and potassium and increases (P < or = 0.01) in glucose, BUN, creatinine, uric acid, cholesterol and LDL compared with baseline. In 12.7% of the patients in the HCTZ group, serum potassium dropped to levels < 3.5 meq/l, which occurred in only 1.4% of the patients who used nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggressive management of acute myocardial infarction.

Acute transmural myocardial infarction is usually caused by a coronary thrombus along with fixed coronary artery stenosis. Myocardial necrosis can be interrupted by the prompt use of pharmacologic and mechanical thrombolysis. Intravenous streptokinase and urokinase have been associated with approximately a 45 percent recanalization rate while the newer agent, recombinant human tissue-type plasminogen activator (rt-PA), has an average lysis rate of 70 percent intravenously. Intracoronary streptokinase and urokinase have a similar 75 percent lysis rate, but with additional costs and morbidity. Percutaneous transluminal angioplasty (PTCA) is often indicated to correct an underlying stenosis, the time of which depends on the experience and expertise of the PTCA team.