Assessment of the Cardiovascular Risk of Olmesartan Medoxomil-Based Treatment: Meta-Analysis of Individual Patient Data.

INTRODUCTION: Results from two long-term studies (ROADMAP and ORIENT) indicated a numerical imbalance in the number of cardiovascular deaths between the olmesartan medoxomil (OM) and placebo groups. OBJECTIVE: Our objective was to conduct an individual patient data meta-analysis to provide more complete information regarding OM-associated cardiovascular risks and/or benefits. METHODS: We created an integrated database based on 191 clinical trials from the OM development program. Events were identified and adjudicated by an independent, blinded clinical events committee. The incidence of major cardiovascular events and total mortality for OM versus placebo/active control were evaluated, and the effect of OM on cardiovascular mortality (main endpoint of interest) and morbidity was calculated using a two-stage approach (Tian method). RESULTS: A total of 46 studies (~27,000 patients) met the US FDA-specified inclusion criteria (phase II-IV randomized, double-blind, placebo- or active-controlled studies [OM-based monotherapy or combination, double-blind period ≥28 days] and adult patients). The incidence of known adjudicated endpoints in the analysis of all studies combined was low among OM (0.11-0.53 %) and placebo/active control (0.08-0.76 %) groups. For cardiovascular mortality, the estimated risk difference (OM vs. control) was 0.00070 (95 % confidence interval [CI] -0.0011 to 0.0024; p = 0.60); the risk difference for each endpoint was <1/1000, with no statistically significant difference between groups. Results were similar with and without ROADMAP and ORIENT. DISCUSSION: The results from this meta-analysis did not show a clinically meaningful or statistically significant difference in cardiovascular risk between OM and the placebo/active control groups, and thus did not corroborate the numerical imbalance observed in ROADMAP and ORIENT.

A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes.

OBJECTIVE: To examine the efficacy and general safety of rivoglitazone, a novel thiazolidinedione, as a treatment for type 2 diabetes in a dose-ranging study over a period of up to 6 months. RESEARCH DESIGN AND METHODS: A 26-week, randomized, double-blind, double-dummy, placebo- and active comparator (pioglitazone 45 mg)-controlled study designed to evaluate the efficacy and safety of once-daily rivoglitazone 1, 2, or 3 mg in subjects with type 2 diabetes. The study was conducted in adults with type 2 diabetes (glycated hemoglobin [HbA(1c)] >or=7.0% and <10.5%) who were either naïve to prior antidiabetes drug treatment or discontinued pre-study antidiabetes medications and were switched to study medication. A total of 441 subjects were randomized, using an equal allocation schedule to one of five treatment arms, including placebo. The primary efficacy measurement was the change in HbA(1c) from baseline to week 26 in the intent-to-treat population (last observation carried forward), for drug treatments minus placebo (placebo-subtracted). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00143520. RESULTS: The incidence of early discontinuations was >50%, with most cases being related to a lack of efficacy (highest on placebo) or adverse experiences (highest on rivoglitazone 3 mg). Rivoglitazone 1, 2, and 3 mg and pioglitazone 45 mg were more effective than placebo in reducing HbA(1c) from baseline to week 26 (placebo-subtracted change from baseline: -0.55% [p = 0.0034], -0.99% [p < 0.0001], -1.10% [p < 0.0001], and -0.59% [p = 0.0016], respectively). In general, all treatments were safe. The most common drug-related adverse events reported with rivoglitazone were peripheral edema and weight gain; incidences increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg. CONCLUSIONS: Rivoglitazone is a potent thiazolidinedione agent with demonstrated glycemic benefits over a 6-month period in subjects with type 2 diabetes. Once-daily doses of 1, 2, and 3 mg rivoglitazone demonstrated HbA(1c) reduction similar or superior to those observed for pioglitazone 45 mg. Limitations in generalizing from this study include a modest sample size and a high rate of discontinuation prior to the last scheduled visit.

Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy.

OBJECTIVE: Hyperglycemia is a risk factor for microvascular complications and may increase the risk of cardiovascular disease in patients with type 2 diabetes. This study tested the LDL cholesterol-lowering agent colesevelam HCl (colesevelam) as a potential novel treatment for improving glycemic control in patients with type 2 diabetes on sulfonylurea-based therapy. RESEARCH DESIGN AND METHODS: A 26-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was carried out between August 2004 and August 2006 to evaluate the efficacy and safety of colesevelam for reducing A1C in adults with type 2 diabetes whose glycemic control was inadequate (A1C 7.5-9.5%) with existing sulfonylurea monotherapy or sulfonylurea in combination with additional oral antidiabetes agents. In total, 461 patients were randomized (230 given colesevelam 3.75 g/day and 231 given placebo). The primary efficacy measurement was mean placebo-corrected change in A1C from baseline to week 26 in the intent-to-treat population (last observation carried forward). RESULTS: The least squares (LS) mean change in A1C from baseline to week 26 was -0.32% in the colesevelam group and +0.23% in the placebo group, resulting in a treatment difference of -0.54% (P < 0.001). The LS mean percent change in LDL cholesterol from baseline to week 26 was -16.1% in the colesevelam group and +0.6% in the placebo group, resulting in a treatment difference of -16.7% (P < 0.001). Furthermore, significant reductions in fasting plasma glucose, fructosamine, total cholesterol, non-HDL cholesterol, and apolipoprotein B were demonstrated in the colesevelam relative to placebo group at week 26. CONCLUSIONS: Colesevelam improved glycemic control and reduced LDL cholesterol levels in patients with type 2 diabetes receiving sulfonylurea-based therapy.

Use of an olmesartan medoxomil-based treatment algorithm for hypertension control.

Hypertension guidelines recommend a stepped-care approach that starts with titration of the initial agent followed by the addition of other agents, as necessary, to achieve goal blood pressure. This study assessed the effectiveness of an antihypertensive treatment algorithm with olmesartan medoxomil as the initial agent. This was a 24-week, open-label trial in patients (N=201) with mean seated diastolic blood pressure of 90-109 mm Hg. Following placebo run-in, all patients received olmesartan medoxomil 20 mg/d for 4 weeks. At subsequent 4-week intervals, the regimen was modified in patients with blood pressure >130/85 mm Hg: up-titration of olmesartan medoxomil to 40 mg/d; addition of hydrochlorothiazide 12.5 mg/d; up-titration of hydrochlorothiazide to 25 mg/d; addition of amlodipine besylate 5 mg/d; and up-titration of amlodipine besylate to 10 mg/d. Patients who achieved blood pressure < or =130/85 mm Hg at any point exited the study with no further follow-up. At Week 24, reductions in blood pressure from baseline were 33.7/18.2 mm Hg. Altogether, 87.7% of patients reached the goal blood pressure of < or =130/85 mm Hg and 93.3% achieved a blood pressure of < or =140/90 mm Hg. Thus, an antihypertensive algorithm with olmesartan medoxomil as the initial agent controlled blood pressure in the majority of patients, but with >60% of patients also requiring the use of a thiazide diuretic or a thiazide and a calcium channel blocker.

Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide.

BACKGROUND: Most patients with hypertension require more than one agent to control blood pressure (BP). The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ). METHODS: This was a randomized, double-blind, factorial design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic blood pressure (SeDBP) of 100 to 115 mm Hg were randomized to one of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20, or 40 mg/day, HCTZ monotherapy (12.5 or 25 mg/day), or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary endpoint was the change in mean trough SeDBP from baseline at week 8. Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses, but did not compare BP reductions with different combination doses. RESULTS: Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure (SeSBP) at week 8 than did monotherapy with either component. All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner. Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg, 20.1/16.4 mm Hg, and 26.8/21.9 mm Hg with placebo, olmesartan medoxomil/HCTZ 20/12.5 mg, and olmesartan medoxomil/HCTZ 40/25 mg, respectively. All treatments were well tolerated. CONCLUSIONS: Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated.