Faculty Bibliography

Despite a better understanding of cardiovascular risk factors and attempts at optimal management, diabetes-related macrovascular events remain a significant cause of morbidity and mortality in the United States and worldwide. The trials to date have validated strict glycemic control as a method to achieve sustained reductions in the rate of nephropathy, neuropathy, and retinopathy due to diabetes. For these microvascular complications, the closer hemoglobin A1c is to normal levels, the better the outcome. Although reducing hemoglobin A1c levels to 7% has been shown to reduce macrovascular events, demonstrating an additional reduction in macrovascular events with tighter glycemic control has been more difficult to achieve. A careful review of recent trials, however, has demonstrated that treatment early in the disease course and the ability to safely maintain lower hemoglobin A1c levels might be critical factors in further reducing macrovascular events. In conclusion, with the introduction of novel antidiabetic agents, future trials using these drugs might be able to definitively establish the safety and efficacy of reducing cardiovascular events with stringent glycemic control; however, the current evidence is inconsistent.

Low-density lipoprotein cholesterol (LDL-C) is currently the primary target in the management of dyslipidemia, and statins are first-line pharmacologic interventions. Adjunct therapy such as niacins, fibrates, bile acid sequestrants, or cholesterol absorption inhibitors may be considered to help reduce cardiovascular risk. This review discusses the need for alternative adjunct treatment options and the potential place for omega-3 fatty acids as such. The cardiovascular benefits of fish consumption are attributed to the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and a variety of omega-3 fatty acid products are available with varied amounts of EPA and DHA. The product types include prescription drugs, food supplements, and medical foods sourced from fish, krill, algal and plant oils or purified from these oils. Two prescription omega-3 fatty acids are currently available, omega-3 fatty acid ethyl esters (contains both EPA and DHA ethyl esters), and icosapent ethyl (IPE; contains high-purity EPA ethyl ester). A pharmaceutical containing free fatty acid forms of omega-3 is currently in development. Omega-3 fatty acid formulations containing EPA and DHA have been shown to increase LDL-C levels while IPE has been shown to lower triglyceride levels without raising LDL-C levels, alone or in combination with statin therapy. In addition, recent studies have not been able to demonstrate reduced cardiovascular risk following treatment with fibrates, niacins, cholesterol absorption inhibitors, or omega-3 fatty acid formulations containing both EPA and DHA in statin-treated patients; thus, there remains a need for further cardiovascular outcomes studies for adjunct therapy.

OPINION STATEMENT: Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events.

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.

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.

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.

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

J Clin Hypertens (Greenwich). 2011;13:722-730. (c)2011 Wiley Periodicals, Inc. 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