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Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.

Nephropathy is a common microvascular complication among patients with type 2 diabetes mellitus and a major cause of kidney failure. It is characterized by albuminuria (≥ 300 mg/d) and a reduced glomerular filtration rate and is often present at the time of diabetes diagnosis after the kidney has been exposed to chronic hyperglycemia during the prediabetic phase. A low glomerular filtration rate (<60 mL/min/1.73 m(2)) is also an independent risk factor for cardiovascular events and death. Detection of diabetic nephropathy during its initial stages provides the opportunity for early therapeutic interventions to prevent or delay the onset of complications and improve outcomes. An intensive and multifactorial management approach is needed that targets all risk determinants simultaneously. The strategy should comprise lifestyle modifications (smoking cessation, weight loss, increased physical activity, and dietary changes) coupled with therapeutic achievement of blood glucose, blood pressure, and lipid goals that are evidence-based. Prescribing decisions should take into account demographic factors, level of kidney impairment, adverse effects, risk of hypoglycemia, tolerability, and effects on other risk factors and comorbidities. Regular and comprehensive follow-up assessments with appropriate adjustment of the therapeutic regimen to maintain risk factor control is a vital component of care, including referral to specialists, when required. [ABSTRACT FROM AUTHOR]

Objective: Women with gestational diabetes mellitus (GDM) maintain a higher risk for recurrent GDM and overt diabetes. Overt diabetes is a risk factor for development of chronic kidney disease (CKD), but GDM alone, without subsequent development of overt diabetes, may also pose a risk for CKD.Research Design and Methods: This cross-sectional analysis included Kidney Early Evaluation Program (KEEP) participants from 2000 to 2009. Patient characteristics and kidney function among three categories (GDM alone, overt diabetes, and no history of diabetes) were compared. The prevalence of microalbuminuria, macroalbuminuria, and CKD stages 1-2 and 3-5 was assessed using logistic regression.Results: Of 37,716 KEEP female participants, 571 (1.5%) had GDM alone and 12,100 (32.1%) had overt diabetes. Women with GDM had a higher rate of microalbuminuria but not macroalbuminuria than their nondiabetic peers (10.0 vs. 7.7%) that was substantially lower than the 13.6% prevalence in diabetic women. In multivariate analysis, women with GDM alone, compared with nondiabetic women, demonstrated increased odds of CKD stages 1-2 (multivariate odds ratio 1.54 [95% CI 1.16-2.05]) similar to the odds for women with overt diabetes (1.68 [1.55-1.82]). In stratified analyses, age, race, BMI, and hypertension modified the odds for CKD stages 1-2 but not CKD stages 3-5 among women with GDM.Conclusions: Women with GDM alone have a higher prevalence of microalbuminuria than women without any history of diabetes, translating to higher rates of CKD stages 1-2. These results suggest that GDM, even in the absence of subsequent overt diabetes, may increase the risk for future cardiovascular and kidney disease. [ABSTRACT FROM AUTHOR]

Hypertension treatment commonly requires multiple agents to achieve target blood pressure (BP). β-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed in clinical practice although few data are available that test their additivity on BP lowering. The efficacy and safety of once-daily extended-release carvedilol (carvedilol CR) combined with the ACEI lisinopril in a double-blind, randomized, factorial design study were studied. Patients (N=656) with stage 1 or 2 hypertension were randomized evenly to 1 of 15 groups for 6 weeks: carvedilol CR monotherapy 20 mg, 40 mg, or 80 mg/d; lisinopril monotherapy 10 mg, 20 mg, or 40 mg/d; or 1 of 9 combinations of carvedilol CR plus lisinopril initiated simultaneously. Primary efficacy measures (assessed by ambulatory BP monitoring [ABPM]) were change from baseline in 24-hour mean diastolic BP (DBP) and in trough (20-24 hours) DBP. Continuous efficacy variables were assessed using analysis of covariance. Whether any combination dose was superior to its monotherapy components was assessed using the Hung AVE procedure. Despite the presence of additional BP lowering observed with most of the combinations compared with their monotherapy components, the Hung AVE test was not significant for either primary efficacy measures. Post hoc analyses of the high-dose combination groups (carvedilol CR/lisinopril regimens of 80/10 mg, 80/20 mg, 80/40 mg, 20/40 mg, and 40/40 mg) showed a significant treatment difference compared with both carvedilol CR 80 mg and lisinopril 40 mg for 24-hour mean DBP but not for trough DBP. With the exception of dizziness, individual adverse events did not increase with ascending doses or combinations. The superiority of initiating combination treatment with carvedilol CR and lisinopril compared with the monotherapy components was not demonstrated with the ABPM measurements. Nonetheless, the post hoc assessment combining all high-dose groups did produce significant 24-hour mean BP reduction when compared with the high-dose monotherapy groups. The tolerability profile of initiating combination therapy was generally comparable to the initiation of treatment with monotherapy. [ABSTRACT FROM AUTHOR]

The kidneys play a major role in the regulation of glucose in humans, reabsorbing 99% of the plasma glucose that filters through the renal glomeruli tubules. The glucose transporter, SGLT2, which is found primarily in the S1 segment of the proximal renal tubule, is essential to this process, accounting for 90% of the glucose reabsorption in the kidney. Evidence has suggested that selective inhibition of SGLT2 induces glucosuria in a dose-dependent manner and may have beneficial effects on glucose regulation in individuals with type II diabetes. Preclinical data with SGLT2 inhibitors, such as dapagliflozin and sergliflozin, show that these compounds are highly selective inhibitors for SGLT2, have beneficial effects on the glucose utilization rate, and reduce hyperglycemia while having no hypoglycemic adverse effects. Clinical research remains to be carried out on the long-term effects of glucosuria and other potential effects of this class of drug. Nonetheless, these compounds represent a very promising approach for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

The prevalence of chronic kidney disease (CKD) continues to increase worldwide as does end stage renal disease. The most common, but not only, causes of CKD are hypertension and diabetes. CKD is associated with a significant increase in cardiovascular (CV) risk as most patients with CKD die of a CV cause. Moreover, CV risk increases proportionally as estimated glomerular filtration rate falls below 60 mL/min. CV causes of death in CKD are more prevalent than those from cancer; as a result, the identification and reduction of CKD is a public health priority. High blood pressure is a key pathogenic factor that contributes to the deterioration of kidney function. The presence of kidney disease is a common and underappreciated preexisting medical cause of resistant hypertension. Therefore, treatment of hypertension has become the most important intervention in the management of all forms of CKD. For this reason, World Kidney Day on March 12, 2009 will emphasize the role of hypertension. [ABSTRACT FROM AUTHOR]

This report updates concepts on hypertension management in patients with diabetes. It focuses on clinical outcomes literature published within the last 3 years and incorporates these observations into modifications of established guidelines. While the fundamentals of treatment and goal blood pressures remain unchanged, approaches to specific patient-related issues has changed. This update focuses on questions such as what to do when a patient has an elevated potassium level when therapy is initiated and whether combinations of agents that block the renin-angiotensin system still be used. In addition, there are updates from trials, just published and in press, that focus on related management issues influencing cardiovascular outcomes in persons with diabetes. Last, an updated algorithm is provided that incorporates many of the new findings and is suggested as a starting point to achieve blood pressure goals. [ABSTRACT FROM AUTHOR]

A panel was convened to discuss current combination therapy for hypertension. Alan H. Gradman, MD, of the Western Pennsylvania Hospital, Temple University School of Medicine (Clinical Campus), Pittsburgh, PA, moderated the discussion. Participants included Matthew R. Weir, MD, University of Maryland School of Medicine, Baltimore, MD, and George L. Bakris, MD, University of Chicago, Chicago, IL. [ABSTRACT FROM AUTHOR]

In a large number of patients with hypertension, > or =2 antihypertensive agents are required to achieve blood pressure (BP) goals. There is good rationale for initial combination therapy based on clinical trials demonstrating that achievement of BP goals within a reasonably short period of time results in fewer cardiovascular events. One approach to attaining BP goals and improving medication adherence is fixed-dose combination therapy, the use of which dates back to the 1960s. Given some of the advantages of renin-angiotensin-aldosterone system (RAAS) blockers in patients with heart disease, kidney disease, and diabetes, many combinations include either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In most studies, however, thiazide diuretics were necessary to achieve goal BP. Calcium channel blockers have also been used in combination with angiotensin-converting enzyme inhibitors to lower BP. Studies are now under way to determine the relative benefits of an RAAS blocker/diuretic compared with an RAAS blocker/calcium channel blocker as initial therapy. [ABSTRACT FROM AUTHOR]

An improvement in the awareness and treatment of hypertension in the United States has occurred, resulting in the best control rates in the world, which unfortunately are far below the goals of Healthy People 2000 or 2010. This failure to achieve blood pressure (BP) goals is attributed to many factors, including an aging population, higher prevalence of kidney disease and obesity, high salt intake, physician inertia to increase dose and number of antihypertensive medications prescribed, and patient nonadherence with medication regimens. Resistant hypertension is defined as a failure to achieve goal BP in patients who adhere to full doses of an appropriate antihypertensive regimen of 3 drugs that includes a diuretic. The problem of resistant hypertension is projected to increase as the population ages. Efforts on the part of the Veterans Administration hospitals and others clearly indicate that a system can be implemented to help increase the percentage of persons in whom BP goal is achieved and reduce the prevalence of resistant hypertension. Medications specific to the problem of resistant hypertension are also under development. This review analyzes the status of hypertension control in the United States, the frequency of associated diseases, and adherence to guidelines; it further discusses strategies to reduce the prevalence of resistant hypertension. [ABSTRACT FROM AUTHOR]

Atenolol and metoprolol succinate, dosed once daily, have different pharmacokinetic profiles. This study tests the hypothesis that differences that are especially noted in the early morning period, when cardiovascular risk is highest, in 24-hour blood pressure (BP) control exist between these 2 beta-blockers. This was a small, randomized open-label study with blinded end point evaluation in 36 hypertensive patients. All participants received hydrochlorothiazide 12.5 mg for 2 weeks before randomization to either 50 mg atenolol or metoprolol succinate given every morning; both treatments were force-titrated to 100 mg/d at 4 weeks. The primary end point was the change in early morning ambulatory systolic BP. Early morning (12 AM-6 AM) systolic BP differences were 3+/-14 mm Hg with atenolol vs -7+/-8 mm Hg with metoprolol succinate (P=.03). The overall 24-hour changes in systolic BP were 1+/-15 mm Hg with atenolol vs -9+/-11 mm Hg with metoprolol (P=.03). In conclusion, metoprolol succinate was more effective in sustaining 24-hour and early morning BP reductions compared with atenolol in a small group of hypertensive patients also treated with once-daily low-dose hydrochlorothiazide. It is possible that differences in outcome between atenolol-based and other therapies may be the result of inadequate dosing of atenolol, a medication that may not be effective for the entire 24-hour period. [ABSTRACT FROM AUTHOR]

Fixed-dosed combination regimens consisting of a calcium channel blocker and an angiotensin II type 1 receptor blocker represent a new addition to the available antihypertensive treatment options. Clinical trials demonstrate that both the dihydropyridine calcium channel blocker amlodipine and angiotensin II receptor blockers are effective agents for the management of hypertension in individuals with or without cardiovascular disease. When combined, these 2 classes of agents have complementary effects on blood pressure, as each targets separate signaling pathways in the vasculature pivotal to the regulation of vascular function. In clinical trials this combination has demonstrated better efficacy, defined by time to reach blood pressure targets as well as levels of blood pressure achieved, compared with the individual agents. In a comparative trial, a combination of amlodipine plus valsartan (an angiotensin II receptor blocker) also produced greater reductions in blood pressure compared with a combination of lisinopril (an angiotensin-converting enzyme inhibitor) and hydrochlorothiazide. The combination of amlodipine and an angiotensin II receptor blocker is well tolerated, including in patients with stage 2 hypertension and the elderly. [ABSTRACT FROM AUTHOR]

Background: The majority of hypertensive patients require combination therapy to achieve BP goals. Guidelines recommend dual therapy in newly diagnosed patients with BP >160/100mm Hg. Calcium channel blocker (CCB)/ACE inhibitor and (beta-blocker ((beta-adrenoceptor antagonists)/diuretic combinations are among regimens considered effective for BP control. ACE inhibitors, beta-blockers, and CCBs are recommended for use in patients after myocardial infarction (MI). Statistical modeling from INVEST (INternational VErapamil-Trandolapril STudy), suggests an association between dual and triple therapy and decreased risk of primary outcome ([PO] first occurrence of death, nonfatal MI, or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD).Objective and Methods: This study explores the utility of dual antihypertensive therapy by reporting BP and cardiovascular outcomes for INVEST patients who predominantly received either a CCB/ACE inhibitor or a beta-blocker/ diuretic regimen.Results: 1170 patients were selected for analysis. After 24 months of treatment, BP control (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI criteria) was 82.1% and 82.6% in the verapamil sustained release (SR) + trandolapril (Ve + Tr) and atenolol + hydrochlorothiazide (At + HCTZ) groups, respectively (p = 0.86). In Ve + Tr compared to At + HCTZ patients, adjusted risk for PO (hazard ratio [HR] 0.63; 95% CI 0.37, 1.05; p = 0.07) and unadjusted risks for secondary outcomes including death (HR 0.70; 95% CI 0.40, 1.25), total MI (HR 0.82; 95% CI 0.35, 1.90), total stroke (HR 0.81; 95% CI 0.25, 2.65) and new diabetes (HR 0.88; 95% CI 0.55, 1.41) were not statistically different.Conclusion: This analysis shows that combination treatment with either Ve + Tr or At + HCTZ is effective in achieving BP control and produces similar outcomes in hypertensive patients with CAD. [ABSTRACT FROM AUTHOR]