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Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy. To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia. A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1. In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups. These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This was a post hoc subgroup analysis of efficacy and tolerability data from the Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial stratified by baseline body mass index (BMI). The BMI subgroup data were also analyzed according to the presence or absence of type 2 diabetes mellitus (T2DM) at baseline. METHODS: The 18-week, prospective, multicenter, open-label, single-arm INCLUSIVE trial evaluated the efficacy and tolerability of a fixed-dose combination of irbesartan/hydrochlorothiazide (HCTZ) in adult hypertensive patients with systolic blood pressure (SBP) that was uncontrolled after >or=4 weeks of monotherapy. Patients received placebo for 4 to 5 weeks, HCTZ 12.5 mg for 2 weeks, irbesartan/HCTZ 150/12.5 mg for 8 weeks, and irbesartan/HCTZ 300/25 mg for 8 weeks. Patients were stratified into BMI subgroups based on values at screening. Normal weight was defined as a BMI or=30 kg/m(2). The primary efficacy end point was the mean change in SBP from baseline (end of the placebo phase) to week 18 in the overall intent-to-treat (ITT) population. Secondary efficacy end points were the mean changes in SBP and diastolic blood pressure (DBP) from baseline to week 18 in each BMI subgroup, the proportions of patients in each BMI subgroup achieving their SBP target (<140 mm Hg [<130 mm Hg for patients with T2DM]) and DBP target (<90 mm Hg [<80 mm Hg for patients with T2DM]), and the mean SBP and DBP responses at the end of each treatment period. RESULTS: The ITT population included 736 patients, of whom 99 (13.5%) were normal weight, 243 (33.0%) were overweight, and 394 (53.5%) were obese. Mean baseline SBP and DBP values were similar across BMI subgroups. Obese patients were generally younger than normal-weight and overweight patients, and numerically more obese patients had T2DM and metabolic syndrome. The mean reductions in SBP and DBP at week 18 were statistically significant in all subgroups (all, P < 0.001); SBP and DBP goals were achieved by a respective 83.8% and 93.9% of normal-weight patients, 75.3% and 87.7% of overweight patients, and 76.9% and 77.2% of obese patients. Rates of SBP/DBP control to <140/90 mm Hg in normal weight, overweight, and obese patients without T2DM were 88.2%, 79.8%, and 80.9%, respectively; the corresponding rates of control to <130/80 mm Hg in patients with T2DM were 50.0%, 41.5%, and 38.5%. CONCLUSION: In this post hoc subgroup analysis of the INCLUSIVE trial, irbesartan/HCTZ combination therapy had comparable antihypertensive efficacy and tolerability regardless of BMI or diabetes status. [ABSTRACT FROM AUTHOR]

BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM. [ABSTRACT FROM AUTHOR]

The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS-Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min -1 , n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy., Competing Interests: G Mancia has received speaker's or consultation fees in the last 2 years from Actavis, Bayer, Böhringer Ingelheim, Covidien, CVRx, Daiichi Sankyo, Ferrer, Lilly, Medtronic Vascular Inc., Menarini Int., Merck Serono, MSD, Novartis, Recordati, Sanofi, Servier, Takeda. AJ Lewin has received research grants in the last 2 years from Abbott Laboratories, AbbVie Inc., ActivX Biosciences Inc., Akros Pharma, Inc., Amarin Pharma, Inc., Amgen Inc., Amylin Pharmaceuticals, AstraZeneca, Bavarian Nordic, Bayer, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Catabasis, Daiichi Sankyo, Elcelyx Therapeutics, Eli Lilly and Company, Esperion Therapeutics, Forest Research Institute, Gilead Sciences, Inc., GlaxoSmithKline, F. Hoffmann-La Roche, Incyte Corporation, Idenix Pharmaceuticals, Isis Pharmaceuticals, Inc., InteKrin Therapeutics, Inc., Kowa Research Institute, Inc., Merck & Co., Inc., Metabolic Solutions Development Company, N-Gene Pharmaceuticals, Novartis Pharmaceuticals Corp., Novo Nordisk, Omthera Pharmaceuticals Inc., Pfizer Inc., Pharmacopeia, Inc., PhaseBio Pharmaceuticals, Phenomix Corporation, Pronova, Sanofi-Aventis, Sanofi Pasteur, Schering-Plough, Shionogi Inc., Surface Logix, Takeda Pharmaceuticals USA, Inc., Theracos, Inc., TransTech Pharma LLC, TWI Biotechnology, Inc., VIVUS, Inc. and XOMA, LLC. P Harvey has received research grants from AstraZeneca, Merck, Pfizer, Boehringer Ingelheim, Bayer, Ipsen, Sanofi Aventis, Novo Nordisk, Novartis, Takeda, Mitsubushi, Solvay, GlaxoSmithKline, Lilly, Lundbeck, Mundi Pharma, Proctor and Gamble Co and Jannsen. SE Kjeldsen has received lecture honoraria from Bayer, Merck Sharp & Dohme, and Takeda, and honoraria for consulting from Bayer and Takeda. G Cha, B Gil-Extremera, and G Villa declare ‘none'. Data collection, analysis and manuscript preparation were sponsored by Bayer HealthCare AG. Editorial assistance was provided by Bill Wolvey of PAREXEL International, which was contracted by the study sponsor (Bayer HealthCare AG).

Objective: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes., Research Design and Methods: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks., Results: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo., Conclusions: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The combination of metformin and a sulfonylurea is commonly used in type 2 diabetes mellitus. Many patients on this combination therapy do not achieve or maintain glycemic targets and require the addition of a third antihyperglycemic agent. Among the options are the sodium glucose cotransporter 2 (SGLT2) inhibitors, a recently developed class of medications that effectively improve glycemic control and are associated with reduction in body weight and blood pressure. This article evaluates a 24-week, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin, added to metformin plus sulfonylurea regimens. Empagliflozin led to significant reductions in glycated hemoglobin and fasting plasma glucose, as well as body weight and systolic blood pressure. Adverse events typically recorded with SGLT2 inhibitors were observed; notably, genital infections occurred in more patients on empagliflozin than placebo. Overall, empagliflozin was well tolerated. These results indicate that SGLT2 inhibitors can be successfully added to metformin plus sulfonylurea regimens. SGLT2 inhibitors are not the only therapeutic option in this clinical situation; however, based on the secondary effects observed in this and other studies, they appear to be of particular value for patients who are obese or overweight.

Objective(s): Evaluate efficacy/safety of olmesartan medoxomil (OM)/amlodipine (AML)/ hydrochlorothiazide (HCTZ) in Hispanic/Latino adults with hypertension., Design: Randomized, double-blind, 12-week, parallel-group study followed by a 40-week open-label extension phase., Setting: Clinical sites (317) in the United States and Puerto Rico., Patients or Participants: Individuals > or =18 years of age with mean seated blood pressure (BP) > or =140/100 or > or =160/90 mm Hg divided into Hispanic/Latino (369) and non-Hispanic/Latino (2122) subgroups., Interventions: Participants were randomized to OM 40/AML 10 mg, OM 40/HCTZ 25 mg, AML 10/HCTZ 25 mg, or OM 40/AML 10/HCTZ 25 mg during the double-blind phase. During the open-label extension, all participants received OM 40/AML 5/HCTZ 12.5 mg; participants not reaching BP goal within 2 weeks were randomly titrated to OM 40/AML 10/HCTZ 12.5 mg or OM 40/AML 5/HCTZ 25 mg, then to OM 40/AML 10/ HCTZ 25 mg after another 2 weeks., Main Outcome Measure: Change in mean seated diastolic BP (SeDBP) from baseline (double-blind phase)., Results: Triple-drug therapy vs the dual therapies resulted in greater mean reduction in SeBP (Hispanic/Latino: 35.0/20.9 mm Hg vs 27.8-30.9/15.3-17.7 mm Hg; non-Hispanic/Latino: 39.0/21.7 mm Hg vs 28.9-31.5/14.6-17.8 mm Hg) and enabled more participants to reach BP goal (Hispanic/Latino: 56.8% vs 40.6%-51.2%; non-Hispanic/Latino: 65.7% vs 33.8%-46.6%) irrespective of ethnicity. The efficacy of triple-drug therapy in achieving BP goal was sustained long-term (40-week open-label extension period) in Hispanic/Latino (63.3%) and non-Hispanic/ Latino (64.2%) participants. Triple-drug therapy was well tolerated in Hispanic/Latino and non-Hispanic/Latino participants., Conclusions: In this study, OM/AML/HCTZ was an effective treatment option in Hispanic/ Latino patients with hypertension.

Objectives: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) aimed to determine the dose-response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension., Methods: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP., Results: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose-response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [-23.8/-16.5 mmHg; P < 0.01 versus placebo (-5.3/-6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.)., Conclusion: N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy.

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Background: Hypertension is often inadequately controlled in older people., Objective: This prespecified subgroup analysis assessed the efficacy and safety of an olmesartan medoxomil (OM) 40 mg/amlodipine besylate (AML) 10 mg/hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the 3 components as dual-combination treatments in participants with hypertension who were <65 and ≥ 65 years of age. Within the ≥ 65 years of age subgroup, efficacy and safety were also summarized for participants ≥ 75 years of age., Study Design: 12-week, multicenter, double-blind, randomized, parallel-group study., Setting: 317 ambulatory care sites in the US and Puerto Rico., Participants: Individuals ≥ 18 years of age with mean seated blood pressure (SeBP) ≥ 140/100 or ≥ 160/90 mmHg off antihypertensive medication on 2 consecutive clinic visits with no recent history of significant cerebrovascular disease, coronary artery disease, heart failure (New York Heart Association class III or IV), severe renal insufficiency, or uncontrolled diabetes (HbA1c >9 %)., Intervention: Participants were randomized, stratified by age, diabetes status, and race to one of four treatment assignments: OM 40/AML 10/HCTZ 25 mg, OM 40/AML 10 mg, OM 40/HCTZ 25 mg, or AML 10/HCTZ 25 mg., Main Outcome Measure: Least squares (LS) mean change from baseline in seated diastolic blood pressure (SeDBP) at week 12 (last observation carried forward) in each age subgroup (prespecified analysis)., Results: Of the 2492 randomized participants in the study (total cohort), 2021 (81.1 %) were <65 and 471 (18.9 %) were ≥ 65 years of age, including 79 (3.2 %) who were ≥ 75 years of age. OM 40/AML 10/HCTZ 25 mg triple-combination treatment resulted in a significantly greater reduction in LS mean SeDBP at week 12 than dual-combination component treatments in participants in both cohorts: <65 years (21.0 vs. 14.2-17.2 mmHg; p < 0.0001) and ≥ 65 years (23.7 vs. 17.3-20.0 mmHg; p ≤ 0.002). Similarly, triple-combination treatment resulted in a greater reduction in LS mean seated systolic blood pressure (SeSBP) at week 12 than dual-combination component treatments: <65 years (38.2 vs. 28.3-31.4 mmHg; p < 0.0001) and ≥ 65 years (39.2 vs. 29.3-31.1 mmHg; p < 0.0001). Triple-combination treatment was more effective than dual-combination treatments in enabling participants to reach SeBP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes, chronic kidney disease, or chronic cardiovascular disease]) in both age subgroups (<65 years: 65 vs. 34-50 %, respectively, p < 0.0001 and ≥ 65 years: 63 vs. 32-39 %; p ≤ 0.0004). All 4 treatments were safe and well tolerated with low discontinuation rates in both age subgroups. There were no clinically relevant differences in the incidence of treatment-emergent adverse events between participants <65 and ≥ 65 years of age receiving triple-combination treatment., Conclusion: Triple-combination treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated and more effective in lowering BP than the component dual-combination treatments in elderly and non-elderly subgroups.

Background: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy., Objective: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU., Methods: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview., Results: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12)., Conclusions: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

The purpose of this phase 2, multicentre, randomized, double-blind, placebo-controlled, 12-week dose-ranging study was to assess the efficacy, safety, and tolerability of the dipeptidyl peptidase-IV (DPP-IV) inhibitor PF-734200 in adult subjects with type 2 diabetes who were on a stable dose of metformin. Men and women with inadequate glycaemic control with metformin as their sole diabetes medication were randomized to placebo or PF-734200 2 mg, 5 mg, 10 mg, or 20 mg every day. A population subset underwent mixed meal tolerance tests (MMTT) at baseline and week 12. A total of 301 subjects were treated. At week 12, PF-734200 doses of ≥5 mg produced a statistically significant reduction in haemoglobin A (1C) (HbA (1c)) compared with placebo. The mean (95% confidence interval) placebo-adjusted changes in HbA (1c) were -0.31% (-0.70 to 0.08), -0.74% (-1.12 to -0.36), -0.70% (-1.02 to -0.38), and -0.75% (-1.07 to -0.43) for the 2 mg, 5 mg, 10 mg, and 20 mg doses, respectively. PF-734200 20 mg significantly reduced glucose area under the curve following MMTT (-12.8% [-22.9 to -2.7]; p=0.003) compared with placebo. The reductions observed with other doses were not statistically significant. PF-734200 was safe and well tolerated at all doses tested when added to metformin. PF-734200 safely and effectively lowered HbA (1c) in subjects receiving metformin. The 20 mg dose provided the greatest improvements in post-prandial glucose., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Aims:   PF-734200 is a potent and selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor. This study assessed the efficacy and safety of PF-734200 at dose rates of 20 and 30 mg/day in subjects with Type 2 diabetes mellitus inadequately controlled on metformin monotherapy., Methods:   This was a placebo-controlled, double-blind, randomized, multicentre, 12 week study. Subjects with Type 2 diabetes mellitus were eligible if screening glycosylated haemoglobin (HbA(1c) ) was 7-11% (53.0-96.7 mmol/mol) and they had been receiving metformin monotherapy for ≥2 months. Subjects receiving metformin and an insulin secretagogue or metformin and thiazolidinedione needed to have a screening HbA(1c) of 6.5-9.5% (47.5-80.3 mmol/mol), measured prior to discontinuing the insulin secretagogue or thiazolidinedione. The primary end-point of the study was a change from baseline to week 12 in HbA(1c) levels., Results:   Baseline characteristics for 289 subjects randomized to PF-734200 or placebo groups were similar (mean age 56.5 years, mean body mass index 32.2 kg/m(2) and mean HbA(1c) 8.2%, 66.1 mmol/mol). In the predefined per protocol data set, least-squares mean HbA(1c) at week 12 was reduced by 0.79 (8.6 mmol/mol 95% confidence interval -1.10 to -0.49, -12.0 to -5.4 mmol/mol) and 0.92% (10.1 mmol/mol; -1.23 to -0.61, -13.4 to -6.7 mmol/mol) in the 20 and 30 mg groups, respectively, compared with placebo. Differences from placebo were statistically significant (P<0.0001), but the differences between the 20 and 30 mg groups were not. The intent-to-treat analysis yielded similar findings., Conclusions:   The HbA(1c) was significantly and meaningfully reduced by both doses of PF-734200, but 20 mg appears to be the more appropriate therapeutic dose for Type 2 diabetes mellitus, contingent upon confirmation by long-term controlled studies., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.

The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.

Objective: Ragaglitazar is a novel insulin sensitizer with dual peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha stimulating activities that improve plasma glucose and lipid profiles. The aim of the present dose-ranging study was to assess the efficacy and safety of ragaglitazar in patients with type 2 diabetes., Research Design and Methods: This study included 177 hypertriglyceridemic type 2 diabetic subjects who participated in a 12-week, double-blind, parallel, randomized, placebo-controlled dose-ranging study (open pioglitazone arm). Subjects received ragaglitazar (0.1, 1, 4, or 10 mg), placebo, or pioglitazone (45 mg). Efficacy parameters included fasting plasma levels of triglycerides and glucose (FPG) along with other lipid levels, A1C, and insulin., Results: Ragaglitazar in doses of 1, 4, and 10 mg resulted in a significant decrease from baseline as compared with placebo in FPG (-48, -74, -77 mg/dl) and triglycerides (-40, -62, -51%), free fatty acids (-36, -54, -62%), apolipoprotein B (-13, -29, -25%), LDL cholesterol (-14 and -19% for 4- and 10-mg groups), and total cholesterol (-16 and -15% for 4 and 10 mg) and a significant increase in HDL cholesterol (20 and 31% for 1- and 4-mg groups, respectively). Changes in triglycerides and FPG for pioglitazone treatment were similar to 1 mg ragaglitazar. Mean A1C values of the 1-, 4-, and 10-mg ragaglitazar and pioglitazone groups were significantly reduced compared with placebo (-0.5, -1.3, -1.1, and -0.3%, respectively). Common adverse events were edema, weight increase, leukopenia, and anemia., Conclusions: Ragaglitazar provided glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided significant improvement in the lipid profile.

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks -9 to -6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of > or =95 but < or =115 mm Hg qualified to enter a 3-week (weeks -6 to -3) placebo run-in low salt diet (50 to 80 mmol Na+/day). Then high salt (200 to 250 mmol Na+/day) was added to the placebo treatment for 3 weeks (weeks -3 to 0). Those patients who demonstrated an increase in SDBP > or =5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na+/day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1,916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 +/- 1.2/7.7 +/- 0.7 mm Hg v 7.7 +/- 0.9/4.8 +/- 0.6 mm Hg, mean +/- SEM, respectively, P < .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 +/- 1.5 v 7.6 +/- 1.3 mm Hg for SSBP and 10.1 +/- 0.6 v 4.8 +/- 0.9 mm Hg for SDBP, P < .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.

Quality of life may be impaired by antihypertensive therapy. Perceived sexual dysfunction by antihypertensive drugs diminishes quality of life and results in noncompliance with antihypertensive therapy. To assess the impact of various classes of antihypertensive therapy vs. combination therapy, self reported adverse reactions were catalogued by gender using COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) of impotence or libido decrease in six randomized, blinded, prospective trials in which subjects received placebo, 5 mg qd-20 mg bid enalapril, 2.5-10 mg qd amlodipine, 6.25-25 mg qd hydrocholorothiazide (HCTZ), bisoprolol 5 mg qd, or a combination of 2.5-10 mg qd bisoprolol/6.25 mg HCTZ. The average duration of drug exposure was 6-14 weeks (range of 1 day to 23 weeks). Comparison among groups was performed using Fisher's exact test. There was no statistical difference between treatment with respect to impotence (p equals 0.688), decrease in libido (p equals 0.970), or overall sexual dysfunction (p equals 0.705) for 1251 men. Of the 661 women studied, decrease in libido was reported in only two subjects. It is concluded that short term exposure to antihypertensive drugs is associated with self reported impotence at no greater prevalence than it is with placebo in men. The combination of bisoprolol/6.25 mg HCTZ is not more likely to be associated with sexual dysfunction than placebo, HCTZ, bisoprolol, enalapril, or amlodipine. Also sexual dysfunction is reported less frequently in women than men. (c)1999 by Le Jacq Communications, Inc.

This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.

Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

Background: This report is part of a larger, multicenter, placebo-controlled study designed to test the effects of low and high salt intake on the antihypertensive action of enalapril maleate or isradipine in salt-sensitive, hypertensive patients., Objective: To present our findings with respect to the effects of race, age, sex, and weight on the blood pressure response to low and high salt intake in salt-sensitive hypertensive patients before randomization into the larger study., Patients and Methods: After 3 week (weeks -9 to -6) of ad lib salt intake (100-200 mmol/d of sodium), 1916 patients whose sitting diastolic blood pressure was between 95 and 115 mm Hg entered a 3-week period (week -6 to -3) of low salt intake (50-80 mmol/d of sodium) and then a 3-week period (week -3 to 0) of high salt intake (200-250 mmol/d of sodium). Of the 1916 patients, 624 were identified as being sensitive to salt by demonstrating an increase in sitting diastolic blood pressure of equal to or more than 5 mm Hg from the low to high salt intake. Of these patients, 367 were white, 156 were black, 92 were Hispanic, 8 were Asian, and 1 was American Indian. Also, 315 were men and 309, women; 351 were 55 years or younger and 273 were older than 55 years; and 195 had a body mass index of 27 or less and 429 had a body mass index higher than 27., Results: The sitting blood pressure decreased with salt restriction and increased with salt load in all groups of patients (P < .001). There were no statistically significant differences in the blood pressure changes to salt changes by race, age, sex, and weight., Conclusions: This large, multicenter study did not demonstrate any statistically significant effect of race, age, sex, and weight on blood pressure response to salt changes in salt-sensitive hypertensive patients.

The safety and efficacy of an extended-release form of diltiazem HCl (diltiazem XR) in patients 55 years or older with mild-to-moderate essential hypertension were examined in a multi-center, double-blind, randomized, placebo-controlled, parallel-group study involving 350 patients with supine diastolic blood pressure (DBP) between 95 mm Hg and 114 mm Hg. Patients were randomized to a once-daily dose of diltiazem XR (240 mg) or placebo; 261 patients received diltiazem XR and 89 received placebo. After 4 weeks, the dose was doubled (to 480 mg) in patients whose supine DBP was > 90 mm Hg, and treatment was continued for another 4 weeks. Diltiazem XR consistently reduced blood pressure (BP) in the study population. At end-point, the mean reduction in supine DBP was 8.65 mm Hg in the diltiazem XR group and 2.75 mm Hg in the placebo group (P < 0.0001). Subgroup analysis confirmed the efficacy of diltiazem XR in men, women, patients between the ages of 55 and 64 years, patients 65 years or older, and non-black patients. Other BP values (supine systolic, standing diastolic, and standing systolic) also were significantly reduced in patients treated with diltiazem XR. BP reduction (supine DBP < or = 90 mm Hg or by > or = 10 mm Hg) was achieved in 58% of patients receiving diltiazem XR compared with 27% of patients receiving placebo. Decreases in apical heart rate were minimal and similar in both groups. No significant differences were noted in adverse events in the diltiazem XR and placebo groups: 36.4% of patients in the diltiazem XR group and 37.1% in the placebo group had no adverse experiences, and 63.6% and 62.9%, respectively, had at least one adverse event. Physical examination findings and laboratory values were clinically unremarkable and comparable in the diltiazem XR and placebo groups. Diltiazem XR given once daily at doses of 240 mg and 480 mg was safe and effective in lowering blood pressure in mature and elderly patients with mild-to-moderate hypertension.

This study used 24-h ambulatory blood pressure (BP) monitoring to investigate the effectiveness of a novel low-dose combination of bisoprolol/hydrochlorothiazide in adult patients with mild to moderate essential hypertension. Thirty-six patients with stable mild to moderate hypertension (sitting diastolic BP 95-114 mmHg) after a placebo run-in phase received oral bisoprolol/hydrochlorothiazide 5 mg/6.25 mg once daily for 4 weeks in a single-blind regimen. At office visits, BP and pulse were measured with statistically significant reductions (p < 0.01) recorded after 2 and 4 weeks of treatment. Twenty-four-h ambulatory BP monitoring at the completion of therapy revealed significant reductions (p < 0.01) in both systolic and diastolic 24-h, daytime, and nighttime BP, compared with the end of the placebo treatment phase. Systolic and diastolic load were also reduced (p < 0.01). The combination was well tolerated, and overall quality-of-life questionnaire scores indicated an improvement after bisoprolol/hydrochlorothiazide therapy (p = 0.02). No clinically significant changes from baseline in laboratory parameters were observed; in particular, serum potassium was unchanged. This is the first study to demonstrate the 24-h effectiveness of the bisoprolol/hydrochlorothiazide 5 mg/6.25 mg combination, using 24-h ambulatory BP monitoring. In addition, antihypertensive therapy with low doses of bisoprolol/hydrochlorothiazide in combination may improve tolerability.

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.

The efficacy and safety of once-daily dosing of isradipine, a new calcium antagonist vasodilator, was evaluated in a multicenter, placebo-controlled trial in hypertensive patients who had supine diastolic blood pressure (SDBP) 100-119 mm Hg. After a 3-week single-blind placebo washout patients randomly received either isradipine, 5 mg once daily, or a matching placebo; if SDBP remained greater than or equal to 95 mm Hg or less than or equal to 10 mm Hg below baseline at four weekly clinic visits, isradipine was increased at weekly intervals by 5 mg once daily up to 20 mg and maintained during weeks 5 and 6. At week 6 mean supine blood pressure 24 hours after dosing had declined from 163 +/- 20/105 +/- 5 (N = 78) to 146 +/- 17/92 +/- 7 mm Hg (N = 60) on isradipine, 14.5 mg once daily, and from 163 +/- 20/105 +/- 6 (N = 85) to 157 +/- 18/99 +/- 10 mm Hg (N = 64) on placebo (P less than .001 between groups). Standing blood pressure decreased from 159 +/- 20/104 +/- 8 to 144 +/- 18/93 +/- 11 mm Hg with isradipine and from 160 +/- 22/105 +/- 9 to 154 +/- 19/101 +/- 11 mm Hg with placebo (P less than .001 between groups) without signs or symptoms of postural hypotension. A SDBP less than or equal to 90 mm Hg or a greater than or equal to 10 mm Hg fall below baseline was achieved in 41 of 78 isradipine-treated (53%) and 18 of 85 placebo-treated subjects (21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Lisinopril (LIS) is a lysine analog of enalaprilat, the active metabolite of enalapril, an angiotensin-converting enzyme inhibitor (ACEI). Unlike enalapril, the precursor of enalaprilat, LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration. Short-term (12 weeks) and long-term (24 weeks) blood pressure control has been studied with LIS, hydrochlorothiazide (HCTZ), and LIS + HCTZ when given once a day. Drug treatment had three phases: (i) 2-4 weeks of single-blind placebo washout; (ii) 12 weeks of double-blind comparison therapy with LIS 20, 40, and 80 mg vs. HCTZ 12.5, 25, and 50 mg, vs. LIS + HCTZ 20 + 12.5, 40 + 25, and 80 + 50 mg; (iii) 13-24 weeks single-blind LIS vs. LIS + HCTZ. Starting double-blind therapy at the lowest dose, all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP (SDBP) less than 90 mm Hg. At the end of 12 weeks of double-blind therapy, uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped. Mean BP reductions (systolic/diastolic, mm Hg) for all three groups after 12 weeks of double-blind comparison therapy were: (i) LIS (n = 162), -16.6/-12.5; (ii) HCTZ (n = 155), -10.4/-6.8; (iii) LIS + HCTZ (n = 74), -23.9/-18.2 with p less than 0.01 for all groups compared to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

The application of sorbent technology to the treatment of uremia has been limited by the inability to adsorb urea adequately. Conversion of urea to ammonium carbonate and adsorption by zirconium phosphate provides a practical means of removing urea. This combination, together with hydrated zirconium oxide and carbon, removes uremic waste products from dialysate. Over 1500 patients are undergoing maintenance hemodialysis with this system. The dialysate composition can be modified for the treatment of patients with acute renal failure. This sorbent system is now being used for the regeneration of peritoneal dialysate. Twenty patients have undergone a total of 90 dialyses, each of 4 to 24 hours duration. One home patient has been solely on this system for two months. The application of sorbent technology to peritoneal dialysis may be the most promising approach to a wearable dialysis system.

A sorbent regenerative dialysate system for peritoneal dialysis has been developed (Pericycle). Clinical results and data demonstrate that the sorbent system provides a suitable dialysate. The sorbents effectively remove uraemic metabolites from the dialysate. Calcium and magnesium removed by the cartridge and glucose metabolised by the patient are replaced by the infusion system. The machine pumps regenerated dialysate into and spent dialysate out of the patients. A pressure sensor in the patient line prevents excessive inflow and outflow pressures by stopping the inflow or outflow pump respectively. The Pericycle provides a simple, safe, portable method for conducting peritoneal dialysis in the home or hospital.

Hypertensive crises were reported in three patients with hypertension associated with underlying renovascular occlusive disease during reduction of antihypertensive therapy. In each case, rebound hypertension was observed during clonidine hydrochloride withdrawal. Therapy with propranolol hydrochloride and diuretics had also been discontinued in two of the three patients. This and other reports of rebound hypertension during clonidine withdrawal are contrasted with the absence of reports of this syndrome in the setting of cessation of beta-adrenergic blockade therapy. This suggests that the discontinuation of clonidine therapy was primarily responsible for the hypertensive crises herein described. It is further concluded that rebound hypertension may follow gradual as well as abrupt reduction of clonidine dosage, and that patients with renovascular hypertension may be at greatest risk.

Sorbent regeneration of peritoneal dialysate has been shown to be feasible in experimental and preliminary clinical studies and provides a realistic basis for the optimization of dialysis therapy and the potential development of an ambulatory dialysis system. Peritoneal dialysis efficiency can be significantly enhanced by continuous dialysate flow techniques and the mass transfer of uremic solutes can be theoretically augmented by the increased dialysis time made possible by a wearable design. Further optimization of end stage renal failure therapy may be achieved by the combined use of various methods for blood purification.

The safety and efficacy of once-daily terazosin hydrochloride administered concomitantly with once-daily atenolol for the treatment of essential hypertension were evaluated in this double-blind, multiclinic, placebo-controlled study. After each patient received 50 mg of atenolol daily for eight weeks, patients with a supine diastolic blood pressure (DBP) of 95 to 110 mm Hg and whose supine DBP had decreased at least 5 mm Hg were randomized to receive either terazosin (plus atenolol) or placebo (plus atenolol) for ten weeks. Patients assigned to the terazosin hydrochloride treatment group received increasing dosages (1,2,5, and 10 mg daily) [corrected] of terazosin at two-week intervals until the maximum dose was reached or until the supine DBP was decreased to less than 90 mm Hg. Terazosin-treated patients (n = 43) had significant mean decreases from the baseline in supine BP (systolic/diastolic = -8.8/-8.5 mm Hg) and standing BP (-10.9/-9.5 mm Hg), whereas the decreases in BP in the placebo-treated patients (n = 49; supine, -2.3/-2.6 mm Hg; standing, -1.4/-1.3 mm Hg) were not significant. When terazosin and placebo were compared, the differences in BP were significant. Terazosin-treated patients had significantly greater decreases in mean percent change of total cholesterol (-4.8%) and low-density lipoprotein plus very-low-density lipoprotein cholesterol (-6.3%) levels, compared with the placebo-treated patients (+0.6% and +1.1%, respectively). Concomitant administration of terazosin and atenolol to patients with essential hypertension was found to be safe and efficacious.

Although both the philosophic and physiologic basis of acupuncture seems fanciful to Western medical thinking, the results obtained in the treatment of certain disease states cannot be lightly dismissed. Its use in the induction of surgical analgesia may have immediate application for Western Medicine. Its mechanism of action is a complete enigma, but information accumulated from research in hypnosis, visceral learning and, most important, the physiology of pain perception may contain clues to the pathophysiologic principles involved. The fact that many disorders for which acupuncture therapy is useful are thought to have a large psychosomatic component only serves to reinforce the Eastern concept of inseparability of mind and body. A great deal of attention is being given to this concept in the current medical literature. In order to define the role of acupuncture in modern medical practice, a more scientific approach in both clinical and basic research is necessary. If acupuncture can be proved safe and efficacious in the treatment of certain diseases, lack of knowledge regarding its mechanism of action should not delay its incorporation into our medical armamentarium.