Efficacy of Amlodipine and Olmesartan Medoxomil in Hypertensive Patients With Diabetes and Obesity

Authors


Henry A. Punzi, MD, Punzi Medical Center, 1932 Walnut Plaza, Carrollton, TX 75006
E-mail: punzimedcenter@aol.com

Abstract

A subgroup analysis of a prospective, open-label, single-arm titration study in patients with hypertension and type 2 diabetes or obesity is reported. The primary end point was the change from baseline in mean 24-hour ambulatory systolic blood pressure (BP) after 12 weeks. Patients received amlodipine 5 mg/d and were uptitrated (if seated [Se] BP was ≥120/80 mm Hg) at 3-week intervals to amlodipine/olmesartan medoxomil 5/20 mg/d, 5/40 mg/d, and 10/40 mg/d. In patients with diabetes and obesity, baseline 24-hour ambulatory BP (±standard deviation) was 145.6±10.4/83.1±9.0 mm Hg and 143.7±9.8/84.9±8.2 mm Hg, respectively, and baseline SeBP was 159.1±11.3/90.3±9.2 mm Hg and 158.2±12.5/94.2±8.5 mm Hg, respectively. Changes from baseline in mean 24-hour ambulatory BP (±standard error of the mean) were −21.5±1.8/−12.6±1.1 mm Hg and 21.6±1.1/13.4±0.8 mm Hg in patients with diabetes and obesity, respectively. Prespecified 24-hour ambulatory BP targets of <130/80 mm Hg, <125/75 mm Hg, and <120/80 mm Hg were achieved by 79.1%, 53.5%, and 39.5% of patients with diabetes and 75.3%, 58.4%, and 43.8% of obese patients, respectively. The SeBP goal of <130/80 mm Hg was achieved by 26.1% of patients with diabetes and <140/90 mm Hg was achieved by 78.1% of obese patients. J Clin Hypertens (Greenwich). 2011;13:422–430. ©2011 Wiley Periodicals, Inc.

The growing epidemic of obesity and obesity-related hypertension parallels the increased prevalence of the metabolic syndrome (MS) and type 2 diabetes.1,2 Among US adults, the incidence of diagnosed diabetes increased by 41% from 4.9 to 6.9 per 1000 from 1997 to 2003 (P<.01).3 Data from the 2003–2004 National Health and Nutrition Examination Survey revealed that up to 76.8% of patients with diabetes and 61.5% of patients with the MS (without diabetes) have hypertension.4 However, only one third of patients with diabetes and just less than one half of patients with the MS receiving antihypertensive treatment achieve a recommended seated cuff blood pressure (SeBP) goal.4 Every 10-mm Hg reduction in SeBP reduces the risk of any diabetes-related cardiovascular complication by 12%.5

Hypertension treatment guidelines in the United States and Europe now recommend initiating treatment with 2 drugs when BP levels are ≥20/10 mm Hg above the desired goal.6–8 Regimens that include angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), plus a thiazide diuretic if necessary, are recommended.6,7 Recent findings challenge the guideline recommendation that favors the use of diuretics. In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, treatment with the ACE inhibitor benazepril combined with amlodipine was superior to benazepril/hydrochlorothiazide (HCTZ) in reducing cardiovascular morbidity and mortality (relative risk, 0.80; 95% confidence interval [CI], 0.71–0.90).9

Several large randomized controlled trials have reported a greater incidence of new-onset diabetes in patients receiving HCTZ, other diuretics, or β-blockers compared with patients receiving ACE inhibitors, calcium channel blockers (CCBs), or ARBs.9–14 As the number of insulin-resistant patients with hypertension continues to increase, it is increasingly important to consider therapies that may prevent new-onset diabetes when choosing antihypertensive agents.14

Another important criterion for the selection of a hypertensive regimen is whether BP control is maintained throughout a 24-hour dosing period. This minimizes the impact of the morning BP surge, which can be an important trigger of cardiovascular events.15 Ambulatory BP monitoring (ABPM) can be used to monitor responses to therapy during a 24-hour period and also during defined time periods.16,17

This report presents a subgroup analysis of the AZOR Trial Evaluating Blood Pressure Reduction and Control (AZTEC), which was a prospective, open-label clinical trial that used ABPM to assess the efficacy and safety of an amlodipine (AML) and olmesartan medoxomil (OM) step-wise titration regimen in patients with hypertension.18 AZTEC showed that this combination regimen was well tolerated and produced robust mean 24-hour ambulatory BP reductions of 21.4/12.7 mm Hg from baseline, which were maintained throughout the dosing interval. The presence or absence of MS was not assessed during enrollment into AZTEC. However, the efficacy of the treatment regimen was evaluated in the present prespecified subgroup analysis of patients with or without type 2 diabetes and post hoc analysis of obese (body mass index [BMI] ≥30 kg/m2) and nonobese patients.

Methods

Study Design and Patients

AZTEC was a 15- to 16-week prospective, open-label, single-arm titration study conducted at 18 clinical sites in the United States. Extensive inclusion and exclusion criteria have been published previously.18 Patients with seated cuff systolic BP (SeSBP) ≥140 mm Hg and ≤199 mm Hg or seated cuff diastolic BP (SeDBP) ≥90 mm Hg or ≤109 mm Hg and a difference of ≤15 mm Hg between SeSBP at the last two consecutive visits during the placebo run-in were eligible. Additionally, participants had a mean daytime 8-hour ambulatory systolic BP (SBP) of ≥135 mm Hg and ≤199 mm Hg and ambulatory diastolic BP (DBP) of <110 mm Hg at the completion of the placebo run-in. Patients with type 1 diabetes were excluded, as were patients with type 2 diabetes unless they were stable on treatment for ≥4 weeks and had a fasting plasma glucose <160 mg/dL at screening. Patients were classified as obese if baseline BMI was ≥30 kg/m2.

The study consisted of a screening phase, followed by a 3- to 4-week placebo run-in, and a 12-week active treatment period in which patients initially received AML 5 mg/d for 3 weeks and were uptitrated as needed at 3-week intervals to AML/OM 5/20 mg/d followed by AML/OM 10/40 mg/d. Patients were uptitrated if SeBP was ≥120/80 mm Hg. Patients with SeBP <120/80 mm Hg remained on their current dosage unless they subsequently became uncontrolled (ie, SeSBP ≥140 mm Hg and/or SeDBP ≥90 mm Hg), in which case they were uptitrated.

Efficacy and Tolerability Assessments

The primary efficacy end point was the change from baseline in mean 24-hour SBP after 12 weeks of active treatment as assessed by ABPM. Secondary end points included the change from baseline in mean 24-hour ambulatory DBP; changes from baseline in mean ambulatory SBP and DBP during the daytime (8 am–4 pm), nighttime (12 am–6 am), and the last 2, 4, and 6 hours of the dosing interval; and the proportions of patients achieving various ambulatory BP targets of <130/80 mm Hg, <125/75 mm Hg, and <120/80 mm Hg during 24 hours, daytime, and nighttime and the last 2, 4, and 6 hours of the dosing period. Additional secondary end points were changes from baseline in mean SeSBP and SeDBP at 12 weeks in the total cohort and by titration period and the proportions of patients achieving SeBP goals of <140/90 mm Hg, <130/80 mm Hg, and <120/80 mm Hg by titration period. Adverse events were assessed at each study visit. Routine clinical laboratory tests and physical examinations were performed at screening and at the end of study or early termination. The safety population comprised all randomized patients who received ≥1 dose of study medication.

Statistical Analysis

The intent-to-treat analysis data set (efficacy cohort) was defined as all patients who received ≥1 dose of active study medication and had a baseline and ≥1 post-baseline BP assessment. Patients with both a baseline and week 12 ABPM measurement were included in all ambulatory BP analyses. Descriptive statistics were used for categoric variables and summary statistics for continuous variables. The primary efficacy variable was assessed using a 1-sample t test performed for the within-group change from baseline to end of study, measured by ABPM. The last-observation-carried-forward (LOCF) method was used for SeBP end points. For BP targets and BP reduction categories, numbers and percentages of patients were provided. Cumulative percentages were calculated using the total number of patients in the treatment cohort as the denominator. Analyses were not performed to determine statistical significance of differences between subgroups.

Results

Of the 325 patients screened, 290 entered the placebo run-in phase and 185 received active treatment. A total of 172 patients had both baseline and week 12 ABPM measurements and were included in the ambulatory BP analysis. Baseline demographics for the efficacy cohort are provided in Table I.

Table I.   Baseline Characteristics of Patients (Efficacy Population) (N=185)
 Obese (n=96)Nonobese (n=89)With Diabetes (n=46)Without Diabetes (n=139)
  1. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation; SeDBP, seated cuff diastolic BP; SeSBP, seated cuff systolic BP. aPatients with ambulatory blood pressure monitoring values for baseline and end of study; obese, n=89; nonobese, n=83; with diabetes, n=43; without diabetes, n=129.

Age, mean±SD (range), y54.9±8.9 (25.0–77.0)58.9±9.4 (36.0–85.0)58.7±8.5 (45.0–77.0)56.2±9.5 (25.0–85.0)
Race, No. (%)
 Caucasian76 (79.2)68 (76.4)39 (84.8)105 (75.5)
 Black17 (17.7)9 (10.1)4 (8.7)22 (15.8)
 Asian3 (3.1)11 (12.4)3 (6.5)11 (7.9)
 Native American/Alaskan0 (0.0)1 (1.1)0 (0.0)1 (0.7)
Sex, No. (%)
 Male44 (45.8)61 (68.5)27 (58.7)78 (56.1)
 Female52 (54.2)28 (31.5)19 (41.3)61 (43.9)
Weight, mean±SD, kg99.5±18.477.1±13.094.2±17.586.9±19.9
Height, mean±SD, cm166.2±13.0169.8±10.8168.3±11.7167.8±12.3
BMI, mean±SD, kg/m235.9±4.926.6±2.533.4±5.730.8±6.1
SeSBP/SeDBP, mean±SD, mm Hg158.2±12.5/94.2±8.5158.3±12.8/91.4±8.6159.1±11.3/90.3±9.2157.9±13.1/93.7±8.3
24-Hour ambulatory SBP/DBP, mean±SD, mm Hga143.7±9.8/84.9±8.2146.1±12.2/86.6±7.6145.6±10.4/83.1±9.0144.6±11.2/86.6±7.3
Hypertension stage, No. (%)
 Stage 139 (40.6)43 (48.3)21 (45.7)61 (43.9)
 Stage 257 (59.4)46 (51.7)25 (54.3)78 (56.1)

Efficacy in the Obese Subgroup

A total of 96 patients (52%) were obese (BMI ≥30 kg/m2) and 89 (48%) were nonobese (BMI <30 kg/m2). Baseline mean ages (±standard deviation [SD]) for obese and nonobese patients were 54.9±8.9 years and 58.9±9.4 years, respectively. Baseline mean ambulatory BP (±SD) for the ABPM cohort was similar for obese and nonobese patients (143.7±9.8/84.9±8.2 mm Hg and 146.1±12.2/86.6±7.6 mm Hg, respectively). Baseline mean SeBP (±SD) was 158.2±12.5/94.2±8.5 mm Hg and 158.3±12.8/91.4±8.6 mm Hg for obese and nonobese patients, respectively. More obese patients had stage 2 hypertension (59.4%) compared with nonobese patients (51.7%). Most patients were uptitrated to the maximum dosage of AML/OM 10/40 mg/d (obese, 72.9%; nonobese, 71.9%).

Mean 24-hour ambulatory SBP (±standard error of the mean [SEM]) reductions from baseline at week 12 were 21.6±1.1/13.4±0.8 mm Hg in obese patients and 21.1±1.2/−12.0±0.7 mm Hg in nonobese patients (all P<.0001) (Figure 1). Significant reductions in ambulatory BP from baseline were seen during the daytime, nighttime, and during the last 2, 4, and 6 hours of the dosing interval for all patients (all P<.0001) (Figure 1). As shown in the 24-hour BP profiles (Figure 2), the AML/OM–based regimen reduced ambulatory BP from baseline across the 24-hour dosing interval.

Figure 1.

 Change from baseline in mean 24-hour ambulatory blood pressure (BP) and during daytime, nighttime, and the last 2, 4, and 6 hours at week 12 for (A) obese and nonobese patients, and (B) patients with and without diabetes. SBP indicates systolic BP; DBP, diastolic BP.

Figure 2.

 Twenty-four–hour blood pressure (BP) profiles in (A) obese patients and (B) patients with diabetes. SBP indicates systolic BP; DBP, diastolic BP.

Seated cuff BP changes from baseline (Figure 3) were statistically significant for both obese and nonobese patients at all treatment dosages. The reductions from baseline in mean SeBP (±SEM) at week 12 (LOCF) were 25.2±1.4/12.3±0.9 mm Hg for obese patients and 22.9±1.6/11.8±0.98 mm Hg for nonobese patients. Uptitration from AML 5 mg/d to AML/OM 10/40 mg/d over the titration algorithm produced sequentially greater mean SeBP reductions from baseline in all patients.

Figure 3.

 Change from baseline in mean seated cuff blood pressure (SeBP) by titration period in (A) obese patients and (B) patients with diabetes. LOCF indicates last observation carried forward; AML, amlodipine; OM, olmesartan medoxomil; SeDBP, seated cuff diastolic BP.

The proportions of obese and nonobese patients reaching prespecified 24-hour ambulatory BP targets are shown in Figure 4. More obese patients achieved these targets compared with nonobese patients. More patients achieved the SeBP goal as the treatment dosage was uptitrated. Similar proportions of nonobese patients achieved BP goals compared with the obese population (Table II).

Figure 4.

 Achievement of ambulatory blood pressure (BP) targets in (A) obese patients and (B) patients with diabetes.

Table II.   Proportion (Percentage) of Patients Achieving SeBP Goals at End of Study and During Titration Period
 AMLa
5 mg
AML/OMa
5/20 mg
AML/OMa
5/40 mg
AML/OMa
10/40 mg
  1. Abbreviations: AML, amlodipine; OM, olmesartan medoxomil; SeBP, seated cuff BP. aCumulative percentages are calculated using the total number of patients in the treatment cohort as the denominator.

Obese, No.96938369
 <140/90 mm Hg21.951.069.878.1
 <130/80 mm Hg3.110.415.624.0
 <120/80 mm Hg1.04.25.210.4
Nonobese, No.89867767
 <140/90 mm Hg25.843.864.075.3
 <130/80 mm Hg4.518.025.837.1
 <120/80 mm Hg0.01.15.67.9
With diabetes, No.46443833
 <130/80 mm Hg4.313.019.626.1
 <120/80 mm Hg2.26.58.78.7
Without diabetes, No.139135122100
 <140/90 mm Hg23.045.365.575.5
 <130/80 mm Hg3.614.420.931.7
 <120/80 mm Hg0.01.44.39.4

Efficacy in the Diabetes Subgroup

Baseline mean ages (±SD) for patients with diabetes (n=46; 25%) and without diabetes (n=139; 75%) were 58.7±8.5 years and 56.2±9.5 years, respectively. Baseline mean ambulatory BP (±SD) for the ABPM cohort was similar for patients with and without diabetes (145.6±10.4/83.1±9.0 mm Hg and 144.6±11.2/86.6±7.3 mm Hg, respectively). Baseline mean SeBP (±SD) was also similar between patients with and without diabetes (159.1±11.3/90.3±9.2 mm Hg and 157.9±13.1/93.7±8.3 mm Hg), with similar rates of stage 2 hypertension. Most patients were uptitrated to AML/OM 10/40 mg/d (with diabetes, 71.7%; without diabetes, 72.7%).

Mean 24-hour ambulatory BP (±SEM) reductions were seen from baseline at week 12 of 21.5±1.8/−12.6±1.1 mm Hg in diabetes patients and 21.3±0.9/−12.8±0.6 mm Hg in nondiabetes patients (all P<.0001) (Figure 1). Significant reductions from baseline in ambulatory BP were seen during the daytime, nighttime, and during the last 2, 4, and 6 hours of the dosing interval for all patients (all P<.0001) (Figure 1). As shown in the 24-hour BP profiles (Figure 2), the AML/OM–based regimen reduced ambulatory BP from baseline across the 24-hour dosing interval.

Seated cuff BP changes from baseline (Figure 3) were statistically significant for both diabetes and nondiabetes patients during each titration period. The end of study changes from baseline in mean SeBP (±SEM) at week 12 (LOCF) were −23.0±2.0/−11.2±1.1 mm Hg for diabetes patients and −24.4±1.3/−12.4±0.8 mm Hg for nondiabetes patients. In all patients, reductions from baseline in mean SeBP increased as treatment was intensified.

In the diabetes population, more patients achieved the prespecified 24-hour ambulatory BP targets of <130/80 mm Hg compared with patients without diabetes (Figure 4). Similar proportions of patients achieved the <125/75 mm Hg and <120/80 mm Hg targets. Cumulative SeBP goal achievement increased as the treatment dosage was uptitrated (Table II).

Safety and Tolerability

The AML/OM–based treatment regimen was well tolerated in each subgroup (Table III). In the safety cohort, 31.4% of patients reported treatment-emergent adverse events (TEAEs) and only 7.6% were considered to be drug-related (DR). In the obese and nonobese subgroups, 9.4% and 5.6% experienced ≥1 DR-TEAE, respectively. The diabetes group and nondiabetes group experienced ≥1 DR-TEAE at a rate of 13.0% and 5.8%, respectively. No cases of hypotension were reported in the study. The most common DR-TEAE, peripheral edema, occurred in 4 of 185 patients in the total study cohort. All 4 of these patients were in the obese subgroup (Table III).

Table III.   Treatment-Emergent AEs
 AML
5 mg/d
AML/OM
5/20 mg/d
AML/OM
5/40 mg/d
AML/OM
10/40 mg/d
Total Cohorta
  1. Abbreviations: AML, amlodipine; OM, olmesartan medoxomil; TEAE, treatment-emergent adverse event. aIndividual adverse events (AEs) were counted only once in the calculation for the entire active treatment period (they were not counted multiple times if they persisted after uptitration to the next dose level).

Obese, No.9693837096
 Patients with any TEAE, No. (%)10 (10.4)25 (26.9)15 (18.1)15 (21.4)33 (34.4)
 Patients with any drug-related TEAE, No. (%)5 (5.2)6 (6.5)2 (2.4)2 (2.9)9 (9.4)
 Discontinuation due to AE, No. (%)1 (1.0)0 (0.0)0 (0.0)0 (0.0)1 (1.0)
Incidence of individual drug-related AEs, No. (%)
 Edema2 (2.1)3 (3.2)1 (1.2)1 (1.4)4 (4.2)
 Dizziness1 (1.0)0 (0.0)0 (0.0)0 (0.0)1 (1.0)
Nonobese, No.8987786489
 Patients with any TEAE, No. (%)7 (7.9)10 (11.5)12 (15.4)14 (21.9)25 (28.1)
 Patients with any drug-related TEAE, No. (%)0 (0.0)3 (3.4)2 (2.6)2 (3.1)5 (5.6)
 Discontinuation due to AE, No. (%)0 (0.0)0 (0.0)1 (1.3)1 (1.6)2 (2.2)
Incidence of individual drug-related AEs, No. (%)
 Edema0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
 Dizziness0 (0.0)1 (1.1)0 (0.0)0 (0.0)1 (1.1)
With diabetes, No.4644393346
 Patients with any TEAE, No. (%)5 (10.9)10 (22.7)7 (17.9)9 (27.3)21 (45.7)
 Patients with any drug-related TEAE, No. (%)2 (4.3)4 (9.1)1 (2.6)1 (3.0)6 (13.0)
 Discontinuation due to AE, No. (%)0 (0.0)0 (0.0)0 (0.0)1 (3.0)1 (2.2)
Incidence of individual drug-related AEs, No. (%)
 Edema0 (0.0)1 (2.3)0 (0.0)0 (0.0)1 (2.2)
 Dizziness1 (2.2)0 (0.0)0 (0.0)0 (0.0)1 (2.2)
Without diabetes, No.139136122101139
 Patients with any TEAE, No. (%)12 (8.6)25 (18.4)20 (16.4)20 (19.8)37 (26.6)
 Patients with any drug-related TEAE, No. (%)3 (2.2)5 (3.7)3 (2.5)3 (3.0)8 (5.8)
 Discontinuation due to AE, No. (%)1 (0.7)0 (0.0)1 (0.8)0 (0.0)2 (1.4)
Incidence of individual drug-related AEs, No. (%)
 Edema2 (1.4)2 (1.5)1 (0.8)1 (1.0)3 (2.2)
 Dizziness0 (0.0)1 (0.7)0 (0.0)0 (0.0)1 (0.7)

Limitations

The present study demonstrated the efficacy of an AML/OM titration regimen in patients with hypertension and who were obese or had diabetes. A majority of the patients with diabetes were treated to the SeBP target <130/80 mm Hg. However, limitations of this study were that long-term efficacy of the treatment could not be determined and the trial was of an open-label and single-arm design. Another limitation was that obese patients were not further stratified by diabetes status. In addition, it was not possible to analyze patient outcomes or to determine the statistical significance of differences between subgroups.

Conclusions

A fixed-dose combination of AML/OM is an effective approach to managing hypertension in all patients, including traditionally difficult-to-treat patients such as those with diabetes and/or obesity.

Discussion

The results of this subgroup analysis parallel those found in the primary study.18 The trial design assessed BP throughout the 24-hour dosing interval and this novel subgroup study allowed an analysis of the effect of the AML/OM–based titration regimen in patients with hypertension and diabetes or obesity. Data of these nature are rarely reported in these classes of metabolically challenged patients. The data showed that BP was reduced and treatment was well tolerated in these patients.

The findings reported here, mean ambulatory BP changes from baseline in the last 6 hours of dosing of −18.0/−11.1 mm Hg (obese subgroup) and −18.7/−10.3 mm Hg (diabetes subgroup), are comparable with those found in the similar Study of Micardis (telmisartan [TEL]) in Overweight/Obese Patients With Type 2 Diabetes and Hypertension (SMOOTH).19 The effect of TEL/HCTZ or valsartan (VAL)/HCTZ fixed-dose therapies on early morning BP using ABPM in high-risk, overweight/obese patients with concomitant hypertension and type 2 diabetes was assessed. Mean changes from baseline in SBP/DBP during the last 6 hours of the dosing interval were −18.4/−9.7 mm Hg in TEL/HCTZ-treated patients and −14.5/−7.7 mm Hg in VAL/HCTZ-treated patients.

In AZTEC, the titration regimen controlled BP during the 24-hour dosing interval in obese patients and SeBP reductions were comparable with a previous study of AML/OM. Previously, up to 50% of obese patients in the 8-week factorial design stage of the Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High BP (COACH) study who received dosages of AML/OM used in the present study achieved the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure goal of <140/90 mm Hg.20 Similar efficacy has been reported in patients receiving VAL, in combination with AML in the Exforge Efficacy and Control in Treatment of Stage 2 Hypertension (EX-EFFeCTS) study.21 In the EX-EFFeCTS study, 53.4% of obese patients with stage 2 hypertension uptitrated to AML/VAL 10/160 mg/d achieved the SeBP goal of <140/90 mm Hg.

The use of ABPM is an important tool to evaluate the efficacy of antihypertensive treatment strategies in patients at risk for cardiovascular events.16,17 In the present study, in patients with diabetes, BP was reduced throughout the 24-hour dosing interval and during the last 6 hours of the dosing period, coinciding with the normal morning BP surge, an event associated with the greatest cardiovascular risk.22

Approximately one quarter of patients uptitrated to AML/OM 10/40 mg/d achieved the recommended SeBP goal of <130/80 mm Hg, a result comparable with the open-label extension of the COACH study where approximately 19% of patients uptitrated to the same dosage achieved this goal.23 The low rate of SeBP goal achievement supports the observation that BP control in patients with diabetes may require multiple antihypertensive agents. Indeed, in the open-label extension of COACH, BP goal achievement was enhanced when HCTZ was added to AML/OM.23 A factorial design study that evaluated the efficacy and tolerability of a triple combination of AML/OM/HCTZ compared with double therapy has recently been published.24

BP control in clinical practice is much worse than that attained in clinical trials. The lack of BP control in the United States has been attributed largely to therapeutic inertia—the failure to manage a chronic condition aggressively enough to bring it under control.25 Fixed-dose combinations are a rational strategy to address patient compliance and clinical inertia,26 particularly given that combination therapy is typically required in obese patients or patients with diabetes who require more stringent recommended BP targets. Excessive pill burden is also likely to reduce compliance to therapy especially in patients with comorbidities. In patients with MS, pharmacologic intervention may be required if lifestyle changes fail to meet therapeutic goals for addressing risk factors such as hypertension, elevated glucose, dyslipidemia, and prothrombotic states. By reducing pill burden and maintaining tolerability, single-pill drug combinations may facilitate treatment of MS.

Most obese patients on monotherapy did not achieve their BP goal. Recently, certain fixed-dose antihypertensive drug combinations (including AML/OM) have been indicated for first-line therapy in patients unlikely to achieve BP goals on monotherapy, thus reflecting the advice recommended by treatment guidelines. Patients in the present study were treated to a more aggressive SeBP target (<120/80 mm Hg) than that recommended by treatment guidelines. Goal attainment was lower in patients with diabetes due to the more stringent target of <130/80 mm Hg. The majority of patients who achieved this goal also received combination therapy.

With no widely recognized treatment targets for ABPM-assessed BP, clinical data of the nature presented here may provide evidence that may help to inform new guidelines. Hypertension treatment targets undergo periodic review and the SeBP target of <130/80 mm Hg for patients with diabetes may also come under further scrutiny given the results of the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.27 The primary end point of the BP-lowering arm of this outcomes study in patients with diabetes was the first occurrence of a major cardiovascular disease event in patients treated with intensive or standard BP-lowering therapy. Reduction of mean SBP to 119.3 mm Hg in the intensive-therapy group, compared with 133.5 mm Hg in the standard-therapy group, did not reduce the rate of the primary outcome. However, the risk of stroke was significantly lower in the intensive-therapy cohort. The United Kingdom Prospective Diabetes Study showed that aggressive antihypertensive treatment in patients with diabetes improved outcomes to a greater extent than improved glycemic control.28,29 Indeed, intensive therapy to target normal glycated hemoglobin in the ACCORD study did not significantly reduce major cardiovascular events but actually increased mortality, leading to early termination of this arm of the clinical trial.30

Acknowledgments

Acknowledgments:  We thank Kathryn Leonard, BSc, and Christopher J. Jones, PhD, of inScience Communications, a Wolters Kluwer business, for providing medical writing support funded by Daiichi Sankyo, Inc.

Acknowledgments

Disclosure:  This study was supported by Daiichi Sankyo, Inc. Henry Punzi, MD, received a research grant from Daiichi Sankyo, Inc. Ali Shojaee, PharmD, William F. Waverczak, MS, and Jen-Fue Maa, PhD are employed by Daiichi Sankyo, Inc.

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