Effect of Hepatic Impairment on the Pharmacokinetics of Nirmatrelvir/Ritonavir, the First Oral Protease Inhibitor for the Treatment of COVID-19.

Nirmatrelvir, a novel, potent, orally bioavailable severe acute respiratory syndrome coronavirus 2 main protease inhibitor, coadministered with ritonavir for pharmacokinetic (PK) enhancement is licensed for the treatment of mild to moderate COVID-19 in individuals at increased risk of progression to severe disease. Cytochrome P450 3A4 is the primary metabolic enzyme responsible for nirmatrelvir metabolism; however, when cytochrome P450 3A4 is inhibited by ritonavir, nirmatrelvir is primarily excreted, unchanged, in urine. Because of intended use of nirmatrelvir among individuals with hepatic impairment, this Phase 1 study (NCT05005312) evaluated the effects of hepatic impairment on nirmatrelvir PK parameters to assess the potential need for any dose adjustments in this population. Participants with normal hepatic function or moderate hepatic impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose, with 100 mg of ritonavir administered 12 hours before, together with, and 12 and 24 hours after nirmatrelvir. Nirmatrelvir median plasma concentrations and systemic exposure measured by area under the plasma concentration-time curve from time zero extrapolated to infinite time and maximum observed plasma concentration values were comparable in both groups. Nirmatrelvir/ritonavir had an acceptable safety profile in both groups, and no clinically significant changes in laboratory measurements, vital signs, or electrocardiogram assessments were observed. Based on these results, no dose adjustment is deemed necessary in patients with moderate hepatic impairment and, by extension, in patients with mild hepatic impairment.

Very high-protein and low-carbohydrate enteral nutrition formula and plasma glucose control in adults with type 2 diabetes mellitus: a randomized crossover trial.

BACKGROUND AND OBJECTIVES: Standard enteral nutrition (EN) formulas can  worsen hyperglycemia in diabetic patients. We hypothesized that altering the proportion of macronutrients in a formula; increasing protein while decreasing carbohydrate concentrations would improve glycemic response. The objective of this study was to demonstrate that an EN formula containing a very high concentration of protein (in the form of whey peptides) and low concentration of carbohydrate provide better control of postprandial blood glucose relative to a very high-protein/higher-carbohydrate formula. SUBJECTS AND METHODS: This was a randomized crossover clinical trial of 12 ambulatory adult subjects with type 2 diabetes. The primary outcome was glycemic response following a bolus of isocaloric amounts of two EN formulas; the secondary outcome was insulin response. Subjects were randomized to the experimental or the control formula, on two separate days, 5-7 days apart. RESULTS: Mean blood glucose concentrations at 10-180 min post-infusion and mean area under the curve for glucose over 240 min post-infusion were significantly lower with the experimental formula than with the control formula (71.99 ± 595.18 and 452.62 ± 351.38, respectively; p = 0.025). There were no significant differences in the mean insulin concentrations over time, insulinogenic indices, and first-phase insulin measurements. CONCLUSIONS: An EN formula containing high-protein and low-carbohydrate loads can significantly improve glucose control in subjects with type 2 diabetes in ambulatory settings as evidenced by observed improved glucose control without significant difference in insulin response.

Human placental membrane as a wound cover for chronic diabetic foot ulcers: a prospective, postmarket, CLOSURE study.

OBJECTIVE: To evaluate the safety and efficacy of a chorioamniotic allograft, used as a wound cover for chronic foot ulcers, in patients with diabetes. METHODS: A multicentre, prospective, postmarket study where eligible patients received up to 11 weekly wound cover applications. Computerised planimetry was used to calculate the diabetic foot ulcer (DFU) area each week. The primary endpoint of the study was wound closure assessment. Secondary endpoints included DFU recurrence and morbidity. RESULTS: A total of 63 patients with 64 ulcers were enrolled, after successful completion of a two-week run-in period. Patients were predominantly male and had risk factors for delayed healing. Mean baseline DFU area was 3.8cm2 (standard deviation (SD): 4.8). After 12 weeks, a total of 19 (40%) DFUs had closed. Results varied by size category, 'small' (≤2.0cm2), 'medium' (>2.0-4.0 cm2), and 'large' (>4.0-25.0 cm2), with higher percentage closure in the 'small' DFU group, compared with the 'medium' and 'large' DFUs (57%, 33%, and 10%, respectively). Of those DFUs that closed, the average closure time was 6.5 weeks. There were no unanticipated adverse events. CONCLUSION: Known risk factors for healing, including DFU size, location and duration, affected the outcomes. However, the results are in line with the literature and support the use of the chorioamniotic allograft in chronic and complex cases.

Comparison of long-term safety of fixed-dose combinations azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide.

This 52-week, randomized, open-label study evaluated long-term safety/tolerability of fixed-dose combination azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs fixed-dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160-190 mm Hg). Initial AZL-M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL-M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment-emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL-M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL-M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed-dose combination AZL-M/CLD showed an encouraging benefit-risk profile when used per standard clinical practice in a titrate-to-target strategy.

Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: an open-label, single-arm, multicenter study.

Long-term safety of a free-tablet combination of nebivolol and valsartan was assessed in a Phase III, open-label trial (NCT01415505). Adults with hypertension entered a 4-week placebo run-in phase, followed by a 52-week treatment phase. Initial dosage (Neb/Val 5/160 mg/d) was titrated up to 20/320 mg/d to achieve blood pressure (BP) goal (JNC7 criteria), with the addition of hydrochlorothiazide (up to 25 mg/d) if needed. Safety and tolerability parameters included adverse events. Efficacy assessments included baseline-to-endpoint change in diastolic BP and systolic BP and the percentage of patients who achieved BP goal. All analyses were performed using descriptive statistics. Study completion rate was 60.4% (489/810). The most frequent reason for discontinuation was insufficient therapeutic response (8.4%). Adverse events were experienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratory tract infection (4.6%). Three (0.4%) deaths occurred during the study; none was considered related to study medication. Mean ± standard deviation changes from baseline at week 52 (observed cases) were -25.5 ± 15.9 mm Hg (systolic BP) and -19.0 ± 8.7 mm Hg (diastolic BP). A total of 75.7% nebivolol/valsartan-treated and 57.8% nebivolol/valsartan/hydrochlorothiazide-treated completers achieved BP goal. Long-term treatment with nebivolol and valsartan in adults with hypertension was safe and well-tolerated.

Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.

IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.

Telmisartan in combination with hydrochlorothiazide 12.5 mg for the management of patients with hypertension.

OBJECTIVE: To compare the efficacy and safety of telmisartan 40 mg (T40) or 80 mg (T80) plus hydrochlorothiazide 12.5 mg (H12.5) single-pill combinations (SPCs) with telmisartan monotherapies, in a pooled analysis of patients with mild to moderate hypertension. METHODS: Six phase 3, double-blind studies of 8 weeks' duration that assessed the T/H12.5 SPC and T40 or T80 monotherapy, were included in the analysis. Data was pooled separately for the two T40 non-responder studies (T40 NR group, two T80 non-responder studies (T80 NR group), and the two factorial design dose-response studies (FD-DR group). RESULTS: After 8 weeks' treatment, the adjusted mean reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the SBP, DBP, and blood pressure (BP) goal rates were significantly higher with the T40/H12.5 SPC than T40 in the T40 NR group and with the T80/H12.5 SPC than T80 in the T80 NR group. In the FD-DR group, the adjusted mean reduction in SBP and DBP, and DBP goal rates were significantly higher for T40/H12.5 versus T40. The percentage of patients with an adverse event was numerically higher with T40/H12.5 versus T40 in the T40 NR group, and was similar in telmisartan monotherapies and the T/H12.5 SPCs in the T80 NR group and FD-DR group. A limitation of this study is the retrospective and pooled nature of the analysis. Also, >75% of patients were <65 years of age, which limits the applicability of the results to older patients. CONCLUSIONS: In patients with mild to moderate hypertension, 8 weeks' treatment with the T/H12.5 SPC is significantly more efficacious than telmisartan monotherapies. The safety and tolerability of the T/H12.5 SPC are comparable to that of telmisartan monotherapy and consistent with that reported in previous studies.

Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.

OBJECTIVES: The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial. BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials. METHODS: Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly. RESULTS: A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2]; NCT01763827).

Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy.

Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy.

Adding Saxagliptin to Metformin Extended Release (XR) or Uptitration of Metformin XR: Efficacy on Daily Glucose Measures.

INTRODUCTION: Saxagliptin added to metformin extended release (XR) and uptitrated metformin XR were evaluated for their impact on daily glucose measurements and their tolerability in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy. METHODS: Patients aged 18-78 years on metformin 850-1,500 mg with glycated hemoglobin (HbA1c) 7.5-11.5% at screening were eligible for this double-blind, active-controlled study. Patients were stabilized on metformin XR 1,500 mg before randomization. Patients with HbA1c 7-11% and fasting plasma glucose (FPG) ≥126 mg/dL after a 4- 8-week lead-in period were randomly assigned to saxagliptin 5 mg + metformin XR 1,500 mg or metformin XR 500 mg + metformin XR 1,500 mg (uptitrated metformin XR). The primary end point was change from baseline to week 4 in 24-h mean weighted glucose (MWG). Secondary end points were changes from baseline to week 4 in 2-h postprandial glucose (PPG) and FPG. RESULTS: At week 4, the adjusted mean ± SE change from baseline in 24-h MWG was -19.0 ± 5.7 mg/dL (95% CI -30.3 to -7.6) for saxagliptin + metformin XR and -8.2 ± 6.0 mg/dL (95% CI -20.0 to 3.7) for uptitrated metformin XR. Mean changes from baseline in 2-h PPG and FPG were numerically greater with saxagliptin + metformin XR versus uptitrated metformin XR. The incidence of adverse events was lower with saxagliptin + metformin XR (17.4%) versus uptitrated metformin XR (31.9%) mainly due to differences in gastrointestinal adverse event incidence (2.2% vs 10.6%, respectively). There were no reports of confirmed hypoglycemia in either group. CONCLUSION: In this 4-week study in patients with T2DM inadequately controlled with metformin monotherapy, saxagliptin added to metformin XR demonstrated a trend for improvement in measures of daily glycemic control, with fewer gastrointestinal adverse events, compared with uptitrated metformin.

Hypertension management: rationale for triple therapy based on mechanisms of action.

An estimated 25% of patients will require 3 antihypertensive agents to achieve blood pressure (BP) control; combination therapy is thus an important strategy in hypertension treatment. This review discusses the triple-therapy combination of an angiotensin receptor blocker (ARB) or direct renin antagonist (DRI) with a calcium channel blocker (CCB) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single-agent therapy. DRIs and ARBs target the renin-angiotensin-aldosterone system (RAAS) at the initial and final steps, respectively, and both classes lower BP by reducing the effects of angiotensin-2; however, ARBs may trigger a compensatory increase in renin activity. Dihydropyridine CCBs target L-type calcium channels and lower BP through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (SNS) and RAAS. Thiazide diuretics lower BP initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the SNS and RAAS. The combination of an agent targeting the RAAS with a CCB and diuretic is rational, and triple combinations of valsartan/amlodipine/hydrochlorothiazide, olmesartan/amlodipine/hydrochlorothiazide, and aliskiren/amlodipine/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual-component combinations. In addition, single-pill, fixed-dose combinations can address barriers to BP control including clinical inertia and poor adherence. Fixed-dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved BP control.

Olmesartan medoxomil-based antihypertensive therapy evaluated by ambulatory blood pressure monitoring: efficacy in high-risk patient subgroups.

Hypertension affects approximately 26% of the world's adult population and is a recognized major risk factor for morbidity and mortality associated with cardiovascular, cerebrovascular, and renal diseases. However, despite the availability of a range of effective antihypertensive agents and a growing awareness of the consequences of high blood pressure (BP), the treatment and control of hypertension remains suboptimal. A number of patient subgroups are categorized as 'high risk' and may have hypertension that is more difficult to treat, including obese individuals, patients with stage 2 hypertension, those with type 2 diabetes mellitus (T2DM), patients with coronary artery disease or a history of stroke, and Black patients. As the benefits of lowering BP in patients with hypertension are unequivocal, particularly in high-risk patients, treating high-risk patients with hypertension to BP goals and maintaining 24-hour BP control is important to help reduce cardiovascular risk and improve outcomes. Although the BP goals recommended in current consensus guidelines for the management of patients with hypertension are based on cuff BP measurements, ambulatory BP monitoring (ABPM) provides a valuable diagnostic tool and allows a more accurate assessment of BP levels throughout the 24-hour dosing period. ABPM is a better predictor of prognosis than office BP measurement and is also useful for assessing whether antihypertensive therapy remains effective in the critical last few hours of the dosing period, which usually coincides with the morning BP surge associated with arousal and arising. ABPM has been adopted by new evidence-based guidelines in the United Kingdom to confirm a suspected diagnosis of hypertension, which is an indication of the growing importance of ABPM in the management of hypertension. This review provides an overview of the efficacy and safety of antihypertensive therapy based on olmesartan medoxomil ± hydrochlorothiazide and amlodipine/olmesartan medoxomil in high-risk patient populations enrolled in studies that reported ambulatory BP endpoints. The studies identified in this review showed that a titrate-to-BP goal strategy using olmesartan medoxomil- or amlodipine/olmesartan medoxomil-based antihypertensive therapy was an effective and well-tolerated approach for maintaining BP control throughout the full 24-hour dosing period in high-risk patients with difficult-to-treat hypertension.

Efficacy of amlodipine/olmesartan medoxomil ± HCTZ in obese patients uncontrolled on antihypertensive monotherapy.

OBJECTIVE: BP-CRUSH (Blood Pressure Control in All Subgroups With Hypertension) was a phase IV, prospective, open-label, multicenter, single-arm, dose-titration study (N = 999). The present subgroup analysis reports the efficacy/safety of up to 20 weeks of treatment with amlodipine (AML)/olmesartan medoxomil (OM) ± hydrochlorothiazide (HCTZ) in obese and non-obese patients with hypertension uncontrolled on antihypertensive monotherapy. RESEARCH DESIGN AND METHODS: Eligible obese (body mass index ≥30 kg/m(2); n = 505) and non-obese (<30 kg/m(2); n = 494) patients were switched to AML/OM 5/20 mg and uptitrated at 4-week intervals to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg + HCTZ 12.5 mg, and AML/OM 10/40 mg + HCTZ 25 mg. Uptitration to higher doses of AML/OM was permitted if mean seated systolic BP (SeSBP) was ≥120 mmHg, or mean seated diastolic BP (SeDBP) was ≥70 mmHg. HCTZ was added if mean SeSBP was ≥125 mmHg, or mean SeDBP was ≥75 mmHg. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00791258 MAIN OUTCOME MEASURES: The primary efficacy endpoint was the cumulative proportion of patients achieving SeSBP <140 mmHg (<130 mmHg for patients with diabetes mellitus) at 12 weeks. Secondary endpoints included seated cuff BP (SeBP) goal rates, ambulatory BP target rates, and mean change from baseline in SeBP and ambulatory BP at weeks 12 and 20. RESULTS: At 12 weeks, 71.6% of obese patients (80.2% non-obese) achieved the primary endpoint of cumulative SeSBP <140 mmHg (<130 mmHg for patients with diabetes). The cumulative SeBP goal of <140/90 mmHg (<130/80 mmHg if diabetes) was achieved by 64.8% and 81.2% of obese patients by weeks 12 and 20, respectively (vs. 77.9% and 88.5% of non-obese patients, respectively). Treatment was well-tolerated, with 26.1% of obese patients (24.9% non-obese) experiencing drug-related treatment-emergent adverse events (TEAEs). There were no serious drug-related TEAEs. CONCLUSION: An AML/OM ± HCTZ treatment regimen provided effective and safe BP control in obese patients with hypertension uncontrolled on monotherapy.

Efficacy of olmesartan medoxomil and hydrochlorothiazide fixed-dose combination therapy in patients aged 65 years and older with stage 1 and 2 hypertension or isolated systolic hypertension.

BACKGROUND: The incidence of hypertension, particularly isolated systolic hypertension, increases with increasing age, as does the risk of fatal cardiovascular disease. A combination antihypertensive therapy regimen may be required to reach recommended BP goals in older patients. OBJECTIVES: This study set out to report blood pressure (BP) data in elderly patients across the subgroups of stage 1 and stage 2 hypertension (prespecified subgroup) and isolated systolic hypertension (ISH) [post hoc]. DESIGN AND SETTING: This was a subgroup analysis of a prospective, open-label study carried out in a multicenter, outpatient setting (e.g. the BeniSILVER [Benicar Efficacy: New Investigation Shows OM Treatment Increasingly Leads to Various Elderly Populations to Safe BP Reductions; ClinicalTrials.gov identifier: NCT00412932] study). The study included 176 patients with a mean age of approximately 72 years; stage 1 hypertension, 60, stage 2 hypertension, 116, and ISH, 98. INTERVENTION: After a 2- to 3-week placebo run-in period, patients were uptitrated every 3 weeks from olmesartan medoxomil (OM) 20 mg daily to OM 40 mg, OM/hydrochlorothiazide (HCTZ) 40 mg/12.5 mg, and OM/HCTZ 40 mg/25 mg, if seated cuff BP (SeBP) was ≥120/70 mmHg. MEASUREMENTS: Measurements included change from baseline in mean 24-hour ambulatory BP and SeBP after 12 weeks of treatment, percentage of patients achieving a cumulative SeBP goal of <140/90 mmHg (stage 1 and stage 2 cohorts) or seated cuff systolic BP (SeSBP) goal of <140 mmHg (ISH cohort), and the incidence of adverse events (AEs). RESULTS: Combination therapy was required by 159 patients. Changes from baseline in mean 24-hour ambulatory BP (± standard deviation [SD]) were -24.2 (± 11.8)/-11.8 (± 6.9) mmHg, -26.5 (± 11.8)/-12.6 (± 6.7) mmHg, and -24.7 (± 12.5)/-11.2 (± 6.4) mmHg in the stage 1, stage 2, and ISH cohorts, respectively (all p < 0.001 vs baseline). Mean SeBP changes (± SD) from baseline in patients titrated to OM/HCTZ 40 mg/25 mg were -24.6 (± 11.4)/-10.5 (± 7.3) mmHg in the stage 1 cohort, -26.4 (± 17.2)/-11.3 (± 9.7) mmHg in the stage 2 cohort, and -21.5 (± 15.6)/-6.8 (± 7.8) mmHg in the ISH cohort (all p < 0.001). The cumulative proportions of patients achieving an SeBP goal of <140/90 mmHg by week 12 were 88.3%, 56.0%, and 72.4% in the stage 1, stage 2, and ISH cohorts, respectively, while 72.4% of patients achieved an SeSBP of <140 mmHg in the ISH cohort. Treatment-emergent AEs ranged from 32.3% to 32.8%, with <3% of patients reporting drug-related hypotension. CONCLUSION: An OM/HCTZ-based titration regimen enabled elderly patients with hypertension to safely reduce BP throughout the 24-hour dosing interval and allowed the majority of these patients to achieve a BP target of <140/90 mmHg or <140 mmHg.

Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial.

BACKGROUND: Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. OBJECTIVE: The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. METHODS: An 8-week, randomized, parallel-group, double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg (T/A; n = 352) with once-daily amlodipine 10 mg (A; n = 354) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension (systolic BP [SBP] >150 mm Hg). RESULTS: Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. CONCLUSIONS: In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).

Single-pill combination of telmisartan/amlodipine in patients with severe hypertension: results from the TEAMSTA severe HTN study.

This 8-week, randomized, double-blind, controlled study compared efficacy and tolerability of telmisartan/amlodipine (T/A) single-pill combination (SPC) vs the respective monotherapies in 858 patients with severe hypertension (systolic/diastolic blood pressure [SBP/DBP] ≥180/95 mm Hg). At 8 weeks, T/A provided significantly greater reductions from baseline in seated trough cuff SBP/DBP (-47.5 mm Hg/-18.7 mm Hg) vs T (P<.0001) or A (P=.0002) monotherapy; superior reductions were also evident at 1, 2, 4, and 6 weeks. Blood pressure (BP) goal and response rates were consistently higher with T/A vs T or A. T/A was well tolerated, with less frequent treatment-related adverse events vs A (12.6% vs 16.4%) and a numerically lower incidence of peripheral edema and treatment discontinuation. In conclusion, treatment of patients with substantially elevated BP with T/A SPCs resulted in high and significantly greater BP reductions and higher BP goal and response rates than the respective monotherapies. T/A SPCs were well tolerated.

Seated cuff blood pressure-lowering efficacy of an olmesartan medoxomil-based treatment regimen in patients with type 2 diabetes mellitus.

BACKGROUND: Hypertension is a common co-morbidity in patients with type 2 diabetes mellitus, and well tolerated, effective therapies are needed to achieve guideline-recommended blood pressure (BP) goals in these patients. OBJECTIVE: The aim of this study was to present the results of a prespecified analysis of key secondary endpoints from a 12-week, open-label, single-arm study evaluating the efficacy and safety of olmesartan medoxomil plus hydrochlorothiazide (HCTZ) in patients with hypertension and type 2 diabetes. STUDY DESIGN AND METHODS: After a placebo run-in period, 192 patients received olmesartan medoxomil 20 mg/day for 3 weeks. If BP remained ≥ 120/70 mmHg, patients were uptitrated at 3-week intervals to olmesartan medoxomil 40 mg/day, olmesartan medoxomil/HCTZ 40/12.5 mg/day, and olmesartan medoxomil/HCTZ 40/25 mg/day. MAIN OUTCOME MEASURE: Endpoints evaluated in this analysis were the change from baseline in mean seated cuff BP (SeBP), proportions of patients achieving SeBP goals, and distribution of SeBP reductions. RESULTS: Mean SeBP was 158.1/90.0 mmHg at baseline. The mean ± standard error of BP reductions at 12 weeks for systolic and diastolic BP were 21.3 ± 1.1 mmHg and 9.8 ± 0.6 mmHg, respectively (p < 0.0001 for each). At the end of the study, the proportion of patients with diabetes achieving the recommended SeBP goal of <130/80 mmHg was 41.1%. CONCLUSIONS: An olmesartan medoxomil ± HCTZ treatment regimen significantly reduced BP from baseline in patients with hypertension and type 2 diabetes. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00403481.

A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil ± hydrochlorothiazide.

In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 ± 11.4 years; baseline blood pressure [BP], 153.7 ± 9.2/91.9 ± 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (± standard error) BP changes from baseline during the titration periods ranged from -14.2±0.4 mm Hg/-7.7 ± 0.3 mm Hg for AML/OM 5/20 mg to -25.1 ± 0.7 mm Hg/-13.7 ± 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. .

A comparison of the efficacy and safety of irbesartan/hydrochlorothiazide combination therapy with irbesartan monotherapy in the treatment of moderate or severe hypertension in diabetic and obese hypertensive patients: a post-hoc analysis review.

Hypertension is difficult to treat in patients with type 2 diabetes mellitus (T2DM) or obesity. Combination therapies are often required to effectively lower blood pressure (BP) and attain BP goals. In this post-hoc analysis of 2 prospective, randomized, controlled studies in patients with uncontrolled or untreated moderate or severe hypertension, the efficacy and safety of treatment with irbesartan/hydrochlorothiazide (HCTZ) and irbesartan was assessed in 2 separate analyses: patients with diabetes (n=143) and by obesity status (n=1125). Patients received irbesartan/HCTZ (150 mg/12.5 mg titrated to 300 mg/25 mg) or irbesartan (150 mg titrated to 300 mg) for 7 (severe hypertension study) or 12 (moderate hypertension study) weeks. Efficacy comparisons between treatment groups were performed using Fisher's exact tests. After 7 to 8 weeks of treatment, systolic BP (SBP)/diastolic BP (DBP) decreased in patients with diabetes by 26.9/17.8 mm Hg and 21.8/15.8 mm Hg after irbesartan/HCTZ and irbesartan treatment, respectively (P [SBP]=0.09, P [DBP]=0.27). In obese patients (n=544), SBP/DBP decreased by 29.4/20.2 mm Hg and 20.1/15.9 mm Hg after irbesartan/HCTZ and irbesartan treatment, respectively (P<0.0001). More patients with T2DM reached the BP goal of <130/80 mm Hg at week 7 to 8 in the irbesartan/HCTZ group than in the irbesartan group (12% vs 5%), although not statistically significant (P=0.22). Significantly more obese patients reached their respective BP goals in the irbesartan/HCTZ group than in the irbesartan group (48% vs 23%; P<0.0001). Treatment-emergent adverse event rates were similar between treatment groups regardless of the presence of diabetes or body mass index (BMI) status. In patients with moderate or severe hypertension and with a BMI ≥ 30 kg/m(2), initial treatment with irbesartan/HCTZ combination therapy was more effective than irbesartan monotherapy.

Management of hypertension in patients with diabetes using an amlodipine-, olmesartan medoxomil-, and hydrochlorothiazide-based titration regimen.

The safety and efficacy of an amlodipine/olmesartan medoxomil (OM)-based titration regimen was assessed in patients with type 2 diabetes mellitus and hypertension. After a 2- to 3-week placebo run-in period, 207 patients received amlodipine 5 mg and were uptitrated to amlodipine/OM 5/20, 5/40, and 10/40 mg and then amlodipine/OM 10/40 mg plus hydrochlorothiazide 12.5 and 25 mg in a step-wise manner at 3-week intervals if the seated blood pressure (BP) remained ≥120/70 mm Hg. The primary end point was the change from baseline in the mean 24-hour ambulatory systolic BP after 12 weeks of treatment. The baseline mean ± SD seated cuff systolic/diastolic BP was 158.8 ± 13.1/89.1 ± 10.1 mm Hg and the mean ± SD 24-hour ambulatory systolic/diastolic BP was 144.4 ± 11.7/81.6 ± 9.8 mm Hg. At week 12, the change from baseline in the mean ± SEM 24-hour ambulatory systolic/diastolic BP was -19.9 ± 0.8/-11.2 ± 0.5 mm Hg (p<0.0001 vs baseline), and 70% of patients had achieved a 24-hour ambulatory BP target of <130/80 mm Hg. At the end of 18 weeks of active treatment in patients uptitrated to amlodipine/OM 10/40 mg plus hydrochlorothiazide 25 mg, the change from baseline in the mean ± SEM seated BP was -28.0 ± 1.5/-13.7 ± 1.0 mm Hg (p<0.0001 vs baseline), with 62% of patients reaching the guideline-recommended seated BP goal of <130/80 mm Hg. Drug-related treatment-emergent adverse events occurred in 19.3% of patients. The most frequent events were peripheral edema (6%), dizziness (3%), and hypotension (2%). In conclusion, this amlodipine/OM-based titration regimen was well tolerated and effectively lowered BP throughout the 24-hour dosing interval in patients with hypertension and type 2 diabetes.