The JNC 7 Approach Compared to Conventional Treatment in Diabetic Patients With Hypertension: A Double‐Blind Trial of Initial Monotherapy vs. Combination Therapy

Abstract

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 β 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.

Current American Diabetes Association, National Kidney Foundation, and Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) guidelines ¹ , ² , ³ state that in participants with hypertension and diabetes mellitus the blood pressure (BP) target goal should be <130/80 mm Hg. This lower goal is associated with additional reductions in cardiovascular morbidity and mortality compared with the goal BP ≤140/90 mm Hg for participants without diabetes. In addition, the two most recent JNC Guidelines on the Prevention, Detection, Evaluation, and Treatment of High BP, JNC VI and JNC 7, suggest consideration of the initial use of low doses of two different antihypertensive medications in appropriate participants, including those with concomitant diabetes mellitus. ³ Because the goal is 10 mm Hg lower for both systolic BP and diastolic BP in participants with diabetes and hypertension than for patients without this comorbidity, it is more likely that these participants will qualify for the JNC 7 criteria of 20/10 mm Hg above target for use of two medications as initial therapy. ³

Participants with hypertension and those with concomitant diabetes in particular, constitute a population in whom there is an unmet medical need. Nationwide, 35.8 % of all participants with hypertension are treated to an appropriate goal BP. ⁴ For participants with concomitant diabetes, fewer are at goal, with one study reporting only 4% at or below a systolic BP goal of 130 mm Hg. ⁵ In the Third National Health and Nutrition Examination Survey database, of participants with hypertension and diabetes receiving antihypertensive therapy, approximately 11% were at the JNC VI goal of <130/85 mm Hg. ⁶

Data demonstrate that, for most participants with hypertension and diabetes, reaching currently recommended goal BP requires multiple therapeutic agents. In the UK Prospective Diabetes Study (UKPDS), ⁷ nearly one third of participants with type 2 diabetes required three or more drugs in the "tight BP control" group. In the Hypertension Optimal Treatment (HOT) trial, ⁸ more than 70% of diabetic subgroup members required at least three drugs to reach a diastolic BP ≤85 mm Hg, and 73% of all participants randomized to the target diastolic BP ≤80 mm Hg required an average of 2.7 antihypertensive medications.

These data underscore the limited utility of initial monotherapy for the treatment of hypertension in this population. Furthermore, in diabetic participants with hypertension not controlled with monotherapy, combination therapy has been shown to be more effective than simply increasing the dose or switching to a different monotherapy. ⁹ Because both the initial use and subsequent titration of monotherapy may be inadequate in diabetic participants with hypertension, the initial use of a low‐dose combination agent or two different antihypertensive medications, which includes one that sensitizes and inhibits the renin‐angiotensin system, may be a helpful treatment strategy.

Evidence from a randomized trial demonstrating clinically meaningful improvement in the efficacy of multiple‐drug initial therapy without a compromise in patient safety should be of interest in the treatment of this high‐risk population. We therefore performed this trial to compare the safety and efficacy of an angiotensin receptor blocker (ARB)/hydrochlorothiazide (HCTZ) combination compared with angiotensin‐converting enzyme (ACE)‐inhibitor monotherapy in hypertensive participants with diabetes.

MATERIALS AND METHODS

This study was a randomized, double‐blind, safety and efficacy study of combination therapy with the ARB losartan (LOS) and HCTZ compared with monotherapy with the ACE inhibitor ramipril (RAM) as antihypertensive therapy in participants with type 2 diabetes and hypertension. The primary objective was to compare the antihypertensive efficacy of combination therapy with LOS/HCTZ 50 mg/12.5 mg (force‐titrated to LOS/HCTZ 100 mg/25 mg at 4 weeks) to RAM monotherapy (force‐titrated every 2 weeks from 2.5 mg to 5 mg to 10 mg to 20 mg). The efficacy was determined by the proportion of participants reaching goal trough sitting diastolic blood pressure (SiDBP) of ≤80 mm Hg after 4 weeks of treatment.

Inclusion and Exclusion Criteria

Participants aged ≥18 years with type 2 diabetes who were receiving at least one antidiabetic medication and taking no more than two antihypertensive medications were eligible for this study. Participants with type 2 diabetes with newly diagnosed hypertension were also eligible if they met BP criteria. Participants with diabetes qualified if hemoglobin A1c was <12% and a random plasma glucose was ≤240 mg/dL. Exclusion criteria were history of malignant hypertension or secondary hypertension of any etiology, cardiovascular events within 6 months of screening, a history of transient ischemic attacks or cerebrovascular accidents, history or physical exam findings consistent with orthostatic hypotension, known or suspected left ventricular dysfunction, acute cardiac ischemia, atrial flutter, atrial fibrillation, or a history of angioedema. Participants taking any concomitant medication for >3 days that could affect BP, including the regular use of nonsteroidal anti‐inflammatory drugs, were excluded, as were participants on concomitant psychotropics or lithium. Laboratory exclusion criteria included those suggestive of renal or hepatic impairment (serum creatine ≥1.5 mg/dL, aspartate aminotransferase or alanine aminotransferase >3 times the upper limit of reference range). Urine levels of albumin and creatinine were measured to rule out macroalbuminuria indicative of overt nephropathy; participants with microalbuminuria were not excluded. The study protocol was approved by the institutional review board/ethics review committee at each institution, and informed consent was obtained from each patient before enrollment.

Blood Pressure Assessment and Design

Recorded BPs represent the means of three consecutive trough SiDBP and trough sitting systolic blood pressure (SiSBP) readings at each visit, in which the individual diastolic readings were within 5 mm Hg of the mean (assessed by mercury sphygmomanometry). Site personnel were trained and certified, and equipment calibrated properly, to perform BP measurements with maximal precision for this study.

After a minimum 7‐day washout period to verify BP at >140/90 mm Hg, participants entered a 2‐week placebo period to assess compliance and ensure BP stability. Earlier randomization was allowed after 1 week of the placebo run‐in phase for participants with an SiDBP 110–120 mm Hg and/or SiSBP 180–200 mm Hg; participants whose BP exceeded either of these ranges were not eligible to continue in the study. Participants meeting all entry criteria after the placebo period were randomized in a 1:1 fashion to LOS/HCTZ 50 mg/12.5 mg or RAM 2.5 mg, both recommended starting doses. After 2 weeks of treatment, participants allocated to LOS/HCTZ 50 mg/12.5 mg remained on this dose (but underwent sham titration). Participants treated with 2.5 mg RAM were force‐titrated to 5 mg RAM. Those treated with LOS/HCTZ 50 mg/12.5 mg were force‐titrated to LOS/HCTZ 100 mg/25 mg at 4 weeks and sham‐titrated at 6 weeks. Participants treated with RAM 5 mg were force‐titrated to 10 mg RAM at 4 weeks. At 6 weeks, participants were titrated again to 20 mg RAM (Figure 1).

Figure 1.

Study design. PBO=placebo; LOS/HCTZ= losartan/hydrochlorothiazide; V=visit; dashed line=sham titration; *patients were stratified based on blood pressure (sitting diastolic blood pressure 90–109 mm Hg or sitting diastolic blood pressure 110–120 mm Hg); †variable taper/washout period of a minimum of 7 days off all hypertension medications before baseline (V2=Week 2) with possible early randomization at V3

Randomization

Participants who met all entry criteria were randomized in a 1:1 fashion to either a LOS/HCTZ or RAM regimen.

Blinding

All bottles were labeled with a single‐panel label with patient's allocation number, lot number, and instructions. Drug disclosure information was provided in a separate sealed envelope for each patient for each container. There were no instances of unblinding, accidentally or otherwise, in this study.

End Points

The primary end point was determined at 4 weeks and was measured by the proportion of participants achieving goal SiDBP ≤80 mm Hg. The secondary objective was the number of participants reaching goal SiSBP (≤130 mm Hg) at 4 weeks. The study was designed to continue beyond that point to study the safety of both medications at the upper limits of recommended doses for the treatment of hypertension and to assess the relative efficacy at the maximal doses of both medications.

An additional objective was to evaluate the overall safety and tolerability of LOS/HCTZ compared with RAM therapy. Safety and tolerability were measured by the overall incidence of adverse experiences (AEs), those AEs deemed to be drug related, and the incidence of prespecified AEs of special interest, including hypotension, dizziness, syncope, hyperkalemia, and worsening renal function as measured by an increase in serum creatinine >0.5 mg/dL from baseline.

Statistics

With a 1:1 randomization scheme and at least 280 participants, the planned power was at least 80% to detect a 10% difference in the proportion of participants reaching goal diastolic BP. Assumptions were that approximately 5% of participants would respond to monotherapy (RAM) and approximately 15% of participants would respond to combination therapy (LOS/HCTZ). The power calculation was based on the normal approximation of Z‐statistics confirmed by simulation on the exact power calculation. To address the primary and secondary hypotheses, the primary approach was modified intention to treat. This analysis included all randomized participants who received at least one dose of double‐blind therapy and had efficacy measurements (trough sitting BP measurements) at baseline and at least once during the treatment period. The last‐observation‐carried‐forward method was employed for participants who discontinued before completing the study or if a planned visit fell outside a predefined visit window. Proportions of patients reaching goal BP (SiDBP ≤80 mm Hg/SiSBP ≤130 mm Hg) between the two treatment groups were compared using a χ ² test. The mean values of all the continuous baseline variables (age, body mass index, duration of hypertension and diabetes, SiDBP, SiSBP, serum glucose, and hemoglobin A1c) between the two treatment groups were compared using a Student t test. Baseline categorical variables such as gender, race, and insulin use were compared using a χ ² test ¹⁰ (version 8.1, 1999–2000, SAS Institute Inc., Cary, NC). All tests of significance are two‐sided and were performed at the 5% level of significance.

RESULTS

Three hundred twelve participants from 53 investigative sites in the United States agreed to participate; 155 and 157 patients entered the study in the LOS/HCTZ and RAM groups, respectively. Table I displays the characteristics of participants assigned to the RAM and LOS/HCTZ arms. The groups were closely matched with respect to demographic characteristics, severity of hypertension, and severity of diabetes. African Americans comprised 21.2% of the sample overall.

Table I.

Patient Characteristics

	LOS/HCTZ* (n=155)	RAM* (n=157)
Female (n [%])	65 (41.9)	61(38.9)
Race (n [%])
African American	35 (22.6)	31 (19.7)
White	95 (61.3)	99 (63.1)
Other	25 (16.1)	27 (17.2)
BMI** (mean ± SD)	33.6±5.9	33.9±6.1
Age (y ± SD)	56.9±10.2	56.0±10.4
Time with hypertension (y ± SD)	10.5±9.6	9.5±8.5
Time with diabetes mellitus (y ± SD)	6.8±6.4	5.8±5.4
Insulin user (n [%])	17 (11.0)	15 (9.6)
SiDBP (mm Hg ± SD)	95.7±5.2	95.9±5.3
SiSBP (mm Hg ± SD)	155.3±12.7	155.0±12.1
Serum glucose (mg/dL ± SD)	167±53.4	158±47.3
HbA1c† (mean %± SD)	7.84±1.4	7.54±1.5
LOS/HCTZ=losartan/hydrochlorothiazide; RAM=ramipril; BMI=body mass index; SiDBP=sitting diastolic blood pressure; SiSBP=sitting systolic blood pressure; HbA1c=hemoglobin A1c; *no statistically significant difference was observed between the two treatment groups; **two participants in the RAM group had missing HbA1c information and were excluded from the calculation; †one patient in the LOS/HCTZ group and one patient in the RAM group did not have measurements of height and weight and were excluded from the BMI calculation

Analysis of the primary end point at 4 weeks demonstrated that 30.5% of the LOS/HCTZ‐allocated participants had attained goal SiDBP compared with 14.4% in the RAM group (p<0.001). Similarly, for the secondary end point, goal SiSBP was achieved in 29.8% and 14.4% in the LOS/HCTZ and RAM groups at 4 weeks, respectively (p<0.001). Figure 2 illustrates the percentages of participants attaining goal SiDBP and SiSBP at each titration interval. Goal attainment for SiDBP and SiSBP was significantly greater for LOS/HCTZ at every time point. In the LOS/HCTZ group, there was a continual increase in the proportion of participants achieving goal at each 2‐week interval, whether the time point followed sham titration (i.e., at 2 weeks and at 6 weeks of therapy) or forced titration (at 4 weeks). At the end of 8 weeks 40.4% of the LOS/HCTZ participants were at goal SiDBP compared with 19.6% in the RAM group (p<0.001). For SiSBP, 45% of participants in the LOS/HCTZ group attained goal compared with 20.9% in the RAM group (p<0.001).

Figure 2.

Percentages of participants attaining goals of therapy for sitting diastolic blood pressure (SiDBP) and sitting systolic blood pressure (SiSBP). LOS/HCTZ=losartan/hydrochlorothiazide; *the primary efficacy measure occurred at 4 weeks.

Figure 3 demonstrates the progressive decline in both SiDBP and SiSBP at each measurement interval in the LOS/HCTZ group. Mean blood pressures were statistically significantly lower in the LOS/HCTZ group than the RAM group at each measurement interval, despite increasing doses of RAM. The dose of LOS/HCTZ was doubled at Week 4 only.

Figure 3.

Changes in mean systolic and diastolic blood pressure at study randomization (Week 0) and each week of titration (ramipril Weeks 2, 4, and 6, losartan [LOS]/hydrochlorothiazide [HCTZ] Week 4). LOS/HCTZ sham‐titrated at Weeks 2 and 6. Error bars represent 95% confidence intervals.

Safety and tolerability were measured by the overall incidence of AEs and those AEs deemed to be drug related by the (blinded) investigator (Table II). The incidence of prespecified AEs of special interest, including hypotension, dizziness, syncope, hyperkalemia, and worsening renal function as measured by an increase in serum creatinine >0.5 mg/dL from baseline are shown in Table III. There were no significant differences in the incidence of AEs between groups.

Table II.

Clinical Adverse Experience (AE) Summary

	LOS/HCTZ (n=155)		RAM (n=157)
	n	%	n	%
≥1 AE	70	45.2	82	52.2
Drug‐related AE*	16	10.3	20	12.7
Serious AE	3	1.9	3	1.9
Serious drug‐related AE*	0	0.0	0	0.0
Death†	1	0.6	0	0.0
Discontinued due to AE	4	2.6	5	3.2
Discontinued due to drug‐related AE*	2	1.3	3	1.9
Discontinued due to serious AE	1	0.6	0	0.0
Discontinued due to serious drug‐related AE*	0	0.0	0	0.0
LOS/HCTZ=losartan/hydrochlorothiazide; RAM=ramipril; *determined by the investigator to be possibly, probably, or definitely drug related; †one patient in the LOS/HCTZ group died due to an acute myocardial infarction that was determined by the investigator to be non‐drug related

Table III.

Adverse Experiences of Special Interest

	LOS/HCTZ (n=155)		RAM (n=157)
	N	%	N	%	p Value
Hypotension (orthostatic)	2	1.3	0	0.0	0.246
Dizziness	6	3.9	6	3.8	1.000
Syncope (loss of consciousness)	0	0.0	1	0.6	1.000
Worsening of renal function*	3	1.9	0	0.0	0.121
Hyperkalemia	2	1.3	1	0.6	0.621
LOS/HCTZ=losartan/hydrochlorothiazide; RAM=ramipril; *worsening of renal function defined as an increase in serum creatinine level of 0.5 mg/dL from baseline or laboratory adverse experience of blood creatinine level increase

DISCUSSION

These data support previous findings documenting the benefit of initiating combination antihypertensive therapy to achieve BP goal in persons with BP >20/10 mm Hg above the goal. ¹¹ In this trial, significant clinically important differences between the efficacy of initial therapy with the combination of LOS/HCTZ were noted compared with traditional monotherapy with RAM in participants with hypertension and type 2 diabetes. The primary finding was that at 4 weeks twice as many participants receiving combination therapy achieved a goal mean trough SiDBP of ≤80 mm Hg compared with titrated RAM monotherapy (30.5% vs. 14.4%, respectively; p<0.001). Moreover, participants achieving goal BP following two steps of combination titration were twice as likely to do so on combination therapy than after four steps of monotherapy titration at 8 weeks (40.4% vs. 19.6%, respectively; p<0.001).

SiSBP followed a similar pattern. The proportion of participants on combination therapy compared with monotherapy who achieved a goal mean trough SiSBP of ≤130 mm Hg at 4 weeks was 29.8% vs. 14.4%, respectively (p=0.001). At 8 weeks, 45% of participants treated with LOS/HCTZ achieved goal SBP, whereas only 20.9% of participants were at goal following four steps of RAM monotherapy (p<0.001).

Inadequate BP control is more prevalent than the successful achievement of goal BP in participants who are otherwise diagnosed and provided with active treatment. As reflected by data from the 1999–2000 National Health and Nutrition Examination Survey, only 35.8% of all participants with hypertension had their BP controlled. ⁴ In this context, it is striking that our study suggests approximately 30% of participants with hypertension and diabetes achieved BP control with initial LOS/HCTZ therapy, and that with one added titration step, an additional 10% of these high‐risk participants were controlled. Generally speaking, combination therapy produces a greater likelihood of achieving BP goals faster than monotherapy although AEs may increase. In this study, there was no difference in AEs with combination therapy compared with monotherapy.

Over the 8 weeks of this trial, participants receiving the combination regimen demonstrated a steady improvement in both systolic and diastolic BP control (Figure 2 and Figure 3), whereas those on monotherapy showed little incremental improvement despite continued dose titrations. As noted, this is consistent with the observation that multiple medications are needed for the effective management of these participants, ⁸ and underscores the inadequacy of a monotherapy treatment paradigm for participants with hypertension and diabetes.

Importantly, the safety and tolerability of the LOS/HCTZ regimen were comparable to monotherapy. The incidences of overall AEs and drug‐related AEs were somewhat lower in the combination group than in the monotherapy group. There were no serious drug‐related AEs reported, and adverse events of special interest were uncommon in general, and similar between treatment groups.

Participants with hypertension and diabetes have a higher risk of major cardiovascular events ¹² , ¹³ , ¹⁴ than either participants with hypertension alone or diabetes alone, and derive substantial benefit from aggressive antihypertensive therapy. ⁷ , ⁸ Nonetheless, some current treatment paradigms may lead to inadequate BP control in a majority of these high‐risk participants; thus, new approaches to treatment are needed. A treatment strategy based on the initial use of a combination of an ARB and a diuretic has the potential to represent an effective and well tolerated approach. Similar data have been obtained with other HCTZ/diuretic combinations, such as β blocker or ACE/HCTZ. The use of a two‐medication approach as initial therapy in these patients may ultimately lead to improved long‐term compliance ¹⁵ , ¹⁶ and thus BP control, with a resultant decrease in cardiovascular morbidity and mortality. Physicians should therefore adhere to the JNC 7 guidelines that suggest two‐drug therapy for initial treatment in high‐risk (e.g., diabetes and high BP) participants.