Effect of Blood Pressure Control on Diabetic Microvascular Complications in Patients With Hypertension and Type 2 Diabetes

Volume 23 Supplement 2
Data, Results, and Consequences of Major Trials With Focus on Type 2 Diabetes
Proceedings from a Symposium

ORIGINAL ARTICLE

Effect of Blood Pressure Control on Diabetic Microvascular Complications in Patients With Hypertension and Type 2 Diabetes

Raymond O. Estacio, MD
Barrett W. Jeffers, MSC
Nancy Gifford, RN
Robert W. Schrier, MD

OBJECTIVE — The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective randomized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications. The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy, retinopathy, and neuropathy.

RESEARCH DESIGN AND METHODS — The 470 hypertensive subjects, defined as having a baseline diastolic blood pressure of >90 mmHg, were randomized to intensive blood pressure control (diastolic blood pressure goal of 75 mmHg) versus moderate blood pressure control (diastolic blood pressure goal of 80–89 mmHg).

RESULTS — The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. During the 5-year follow-up period, no difference was observed between intensive versus moderate blood pressure control and those randomized to nisoldipine versus enalapril with regard to the change in creatinine clearance. After the first year of antihypertensive treatment, creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria. In contrast, patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5–6 ml · min^–1· 1.73 m^–2 per year throughout the follow-up period whether they were on intensive or moderate therapy. There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria (25% intensive therapy vs. 18% moderate therapy, P = 0.20) or microalbuminuria to overt albuminuria (16% intensive therapy vs. 23% moderate therapy, P = 0.28). Intensive therapy demonstrated a lower overall incidence of deaths, 5.5 vs. 10.7%, P = 0.037. Over a 5-year follow-up period, there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy. In addition, the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy.

CONCLUSIONS — Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period. The more intensive blood pressure control decreased all-cause mortality.

Diabetes Care 23 (Suppl. 2):B54–B64, 2000

There is epidemiological evidence in type 2 diabetes for a correlation between blood pressure and vascular complications (1–11). In the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial, Mehler et al. (12) demonstrated an independent association between the presence of hypertension with diabetic nephropathy, retinopathy, neuropathy, and cardiovascular disease (CVD). The correlation between blood pressure and renal function in type 2 diabetes has been shown to be continuous, even below the accepted cutoff point for the definition of hypertension (140/90 mmHg) (13). In this regard, the Sixth Report of the Joint National Committee (JNC-VI) on Prevention, Detection, Education, and Treatment of High Blood Pressure recommended a blood pressure goal of <130/85 mmHg in diabetic patients as compared with <140/90 mmHg in nondiabetic patients (14). Recently, results from a number of clinical trials evaluating the effect of different blood pressure treatment goals on diabetic outcomes mainly focusing on CVD have been published (15,16). In a secondary analysis of the 1,501 type 2 diabetic patients studied in the Hypertension Optimal Treatment Trial, CVD events were significantly less common in patients randomized to a goal diastolic blood pressure of <80 mmHg compared with patients randomized to a goal of <90 mmHg (15). Among the 1,148 hypertensive type 2 diabetic patients studied in the U.K. Prospective Diabetes Study (UKPDS), significantly fewer diabetic micro- and macrovascular complications and diabetic-related deaths occurred in the group with a mean blood pressure of 144/82 mmHg compared with the group with a mean blood pressure of 154/87 mmHg. However, these results do not address whether an even lower blood pressure, similar to that recommended by the JNC-VI committee, would be even more beneficial. The ABCD Trial is a prospective randomized trial in 950 type 2 diabetic patients that examines this question (17–19).

The 470 patients in the hypertensive cohort of the ABCD Trial, defined as a diastolic blood pressure >90 mmHg, were randomized to either a moderate (diastolic blood pressure goal of 80–89 mmHg) or intensive (diastolic blood pressure goal of 75 mmHg) blood pressure reduction goal. The study also evaluated the effects of a long-acting calcium channel antagonist (nisoldipine) versus an ACE inhibitor (enalapril). The primary end point of the study was change of creatinine clearance, but the effects of the different blood pressure levels on retinopathy, neuropathy, and CVD were also addressed. Recently, we reported in this same cohort that treatment with the ACE inhibitor enalapril was associated with significantly fewer cardiovascular outcomes (specifically myocardial infarctions) than in patients treated with the long-acting calcium channel blocker (CCB) nisoldipine (20). The current article focuses on the effect of moderate (mean 138/86 mmHg) versus intensive (mean 132/78 mmHg) blood pressure control using either nisoldipine or enalapril in hypertensive type 2 diabetic patients with nephropathy, retinopathy, and neuropathy followed for over 5 years.

RESEARCH DESIGN AND METHODS

Design
There were 470 hypertensive type 2 diabetic subjects in the ABCD Trial randomized to moderate versus intensive antihypertensive treatment (18). Within the moderate (diastolic blood pressure goal of 80–89 mmHg) and intensive (diastolic blood pressure goal of 75 mmHg) treatment groups, patients were further randomized to receive either nisoldipine or enalapril as the primary antihypertensive medication. The primary objective of the study was to determine the effect of moderate versus intensive blood pressure control on the change in creatinine clearance. The ABCD Trial design has been described previously (18).

Participants
Subjects in the ABCD Trial were between the ages of 40 and 74 years at the time of recruitment and were identified from Diagnosis Related Group, pharmacy, and billing lists from participating health care systems in the Denver metropolitan area. All patients in the ABCD Trial were diagnosed with type 2 diabetes according to the criteria based on the World Health Organization report of 1985 (21). All enrolled hypertensive subjects had a diastolic blood pressure >90 mmHg and were off all antihypertensive medications at the randomization visit. Patients were excluded if they had a known allergy to dihydropyridines or ACE inhibitors, had a myocardial infarction or cerebral vascular accident within the previous 6 months, had coronary artery bypass surgery within the previous 3 months, had unstable angina pectoris within the previous 6 months, had Class III or IV New York Heart Association classification of congestive heart failure, demonstrated an absolute need for ACE inhibitors or CCBs, received hemo- or peritoneal dialysis, and/or had a serum creatinine level >3 mg/dl.

Randomization and study therapy
During the 7- to 11-week single-blind placebo run-in period, all baseline studies were performed. After the placebo run-in, the mean baseline diastolic blood pressure was determined at two separate visits for each patient. Subjects with a mean baseline diastolic blood pressure >90 mmHg were designated to have hypertension. These patients were randomized into two treatment arms consisting of intensive treatment with a diastolic blood pressure goal of 75 mmHg and moderate treatment with a diastolic blood pressure goal of 80–89 mmHg (Fig. 1). Patients were randomized to either nisoldipine 10 mg/day, titrated to 20, 40, and then 60 mg/day (plus placebo for enalapril), or enalapril 5 mg/day titrated to 10, 20, and then 40 mg/day (plus placebo for nisoldipine), as the initial antihypertensive medication. If the single study medication alone did not achieve the target blood pressure, then open-labeled antihypertensive medications were added in a step-wise fashion, initially with metoprolol, then hydrochlorothiazide, until the target blood pressure was achieved. Additional antihypertensive medications were added at the discretion of the medical director but did not include a calcium channel antagonist or ACE inhibitor.

Figure 1—Study design of the hypertensive cohort of the ABCD Trial. DBP, diastolic blood pressure.

Study end points
The primary end point was the effect of intensive versus moderate blood pressure control on the change in 24-h creatinine clearance, which was assessed every 6 months. Secondary end points included the effect of intensive versus moderate blood pressure control on cardiovascular events, retinopathy (as determined by stereoscopic retinal photographs) (22), clinical neuropathy (23), and urinary albumin excretion (UAE) (24). The effects of nisoldipine versus enalapril on these end points were also evaluated. Details of the study end point determinations have been previously described (18).

At 67 months after the first patient was randomized into the study, the Data Safety Monitoring Committee (DSMC) observed a significant difference in cardiovascular events (specifically myocardial infarctions) between study drugs in the hypertensive cohort, which has been discussed previously (20). Based on this information, the DSMC recommended switching the nisoldipine-treated patients in the hypertensive group to enalapril treatment.

Renal end points
Glomerular filtration rates were estimated from 24-h creatinine clearances standardized for body surface area obtained at baseline, then every 6 months during the course of the study (18). Given the near-normal creatinine clearance for the present group of diabetic patients, minimal creatinine tubular secretion would be expected. Moreover, as reported earlier, iothalamate clearances in 200 patients correlated closely with creatinine clearance (25). UAE was measured using radioimmunoassay techniques from 24-h or overnight collections at baseline and every 2 months thereafter following randomization. Urinary albumin, sodium and potassium excretion, and creatinine clearance were measured using standard procedures in the Renal Laboratory at the University of Colorado Health Sciences Center.

Retinopathy end points
Retinopathy was staged using the Modified Airlie House Classification of Diabetic Retinopathy, as adapted for the Diabetes Control and Complications Trial by the Wisconsin Retinal Reading Center. Seven-field stereoscopic fundus photographs were taken on-site at baseline then at year 2 and 5 by a technician trained by the Wisconsin Center. All retinal films were interpreted and graded by the Fundus Photograph Reading Center at the University of Wisconsin without the knowledge of the treatment arm. The graders used the protocol of the Early Treatment Diabetic Retinopathy Study (ETDRS) (22). The overall level of severity of retinopathy was determined for each patient according to the ETDRS interim scale (26), in which a scale of 23 steps is used to represent the overall extent of retinopathy in both eyes. The development of clinically important retinopathy is defined as a change of at least three steps from baseline measurements.

Diabetic neuropathy
The presence and progression of diabetic neuropathy was assessed according to the criteria established by Dyck (27). These criteria include neurological symptoms score, neurological disability score, autonomic nervous system testing with heart rate response to deep breathing, and quantitative sensory examination performed at baseline and then at year 2 and 5.

Cardiovascular disease
An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular events. Cardiovascular outcomes were defined as follows: 1) death due to cardiovascular events (sudden death, progressive heart failure, fatal myocardial infarction, fatal arrhythmias, cerebral vascular accidents, and ruptured aortic aneurysm), 2) nonfatal myocardial infarction, 3) nonfatal cerebral vascular accident, 4) heart failure requiring hospital admission, and 5) pulmonary infarction. The end point committee reviewed all hospital admissions that appeared to be related to a cardiovascular event.

Statistics
The Statistical Analysis Software (SAS) system was used for all statistical analyses. Two statistical procedures were used when examining differences in baseline characteristics and complications between the intensive and moderate therapy groups and between the nisoldipine and enalapril groups. When the baseline characteristic or complication was continuous (age, duration of hypertension, duration of diabetes, glycohemoglobin, systolic blood pressure, diastolic blood pressure, BMI, pack-years smoking, and years of education), a two-sample t test was used. When the baseline characteristics were clearly non-Gaussian distributed, nonparametric analyses or parametric analyses on a suitably transformed variable were performed. A ² analysis was used when the baseline characteristic or complication was categorical (sex, presence of overt albuminuria, presence of diabetic retinopathy, presence of diabetic neuropathy, and presence of CVD).

A general linear mixed model was used when evaluating the effects of blood pressure control over time on kidney measures (creatinine clearance, serum creatinine, and log UAE). Log UAE was used instead of UAE because of the non-Gaussian nature and large variance of UAE values. The general linear mixed model is ideally suited for unbalanced repeated-measures and longitudinal data. To further enhance understanding of the longitudinal effects of blood pressure control on kidney function, t tests were carried out at each time point. These tests are especially helpful in describing interactive effects between blood pressure control and time. Progression of retinopathy and neuropathy were analyzed using a ² test. Statistical significance was defined using = 0.05, and all values are reported as mean ± SEM.

RESULTS — There were 470 hypertensive type 2 diabetic subjects included in the study. Tables 1 and 2 show the baseline characteristics and prevalence of complications of the study population according to those patients randomized to intensive versus moderate antihypertensive therapy and those randomized to nisoldipine versus enalapril, respectively. The baseline characteristics and interrelations of the ABCD population have been reported in several publications (12,28–34).

During the course of the study, a blood pressure separation was maintained between the intensive and moderate therapy groups, which was achieved within the first 6 months and then maintained for the remainder of the follow-up period (Fig. 2) (P < 0.001). The average blood pressure for the last 4 years of follow-up was 132/78 mmHg for the intensive antihypertensive therapy group and 138/86 mmHg for the moderate antihypertensive therapy group. Figure 3 shows the mean systolic and diastolic blood pressure during the follow-up period for patients randomized to nisoldipine versus enalapril in the intensive and moderate arms of the study. There was no statistical difference in either group between the enalapril and nisoldipine treatments. Over this time period, there was no difference between glycosylated hemoglobin and total cholesterol when comparing the intensive versusmoderate therapy group (Fig. 4A) and individuals randomized to nisoldipine versus enalapril (Fig. 4B). HDL cholesterol, triglyceride, and LDL cholesterol levels between the two groups were also not significantly different (data not shown).

Figure 2—Systolic (A) and diastolic (B) blood pressures according to intensive versus moderate therapy throughout 5 years. The t tests at each time interval revealed that a significant blood pressure separation occurred after 6 months between the two interventions (P < 0.001).

Figure 3—Blood pressures throughout the 5 years according to enalapril versus nisolipine therapy for those in the intensive (A) therapy group and the moderate (B) therapy group. The t tests at each time interval revealed no significant difference between the therapies

The patients were on their initial randomized therapy an average of 70% of the study time. There was no significant difference in the number of patients discontinuing study medication between those randomized to nisoldipine and enalapril. The reasons for discontinuing study medication include the following: adverse events (54 patients on nisoldipine and 41 patients on enalapril); "voluntary" reasons (38 patients on nisoldipine and 41 on enalapril, for reasons that include recommended to change to an ACE inhibitor by their primary care physician, moved, or patient initiated); and death or cardiovascular events (50 patients on nisoldipine and 41 on enalapril). Patients taken off enalapril (blinded) and placed on open-label enalapril were still considered "off" study medication.

Figure 4—Mean total cholesterol (normal range 130–200 mg/dl) and glycohemoglobin (normal range 4.2–7.0%) values over 5 years for intensive versus moderate therapy (A) and nisoldipine versus enalapril therapy (B). The t tests at each time interval revealed no significant difference between the therapies.

Nephropathy
Creatinine clearance. Repeated-measures analyses demonstrated that the change in creatinine clearance and the log UAE throughout the 5-year follow-up period were not significantly different between the intensive versus moderate therapy groups (Fig. 5). Using a mixed model to perform a repeated-measures analysis also revealed that there is no difference between intensive and moderate therapy as far as slope of creatinine clearance over time. In the mixed model, the interaction between time and intervention (intensive vs. moderate) was not significant. Subanalyses of creatinine clearance in patients starting with normoalbuminuria and microalbuminuria revealed no differences between the intensive and moderate antihypertensive therapy (Fig. 6). Virtually the entire decline in the mean creatinine clearance occurred within the first year of the study for both the intensive and moderate therapy groups with either normo- or microalbuminuria at baseline. Table 3 includes the percentage of patients that progressed from normoalbuminuria to microalbuminuria or microalbuminuria to overt albuminuria. There was no significant difference between the intensive and moderate therapy groups.

Figure 5—Mean creatinine clearance and log UAE according to intensive versus moderate blood pressure control. The number of patients completing the creatinine clearance measurements at each time period is listed on the bottom. The t tests evaluating change from baseline at each time interval revealed no significant difference between the therapies.

Figure 6—Mean creatinine clearance according to intensive versus moderate therapy for patients with normoalbuminuria and microalbuminuria at baseline. The number of patients completing the creatinine clearance measurements at each time period is listed on the bottom. The t tests evaluating change from baseline at each time interval revealed no significant difference between the therapies.

Compared with those patients with normo- or microalbuminuria at baseline, patients with overt albuminuria (>300 mg/day) had a significant and continuous decline in creatinine clearance throughout the 5-year period in both the intensive therapy (n = 46) and the moderate therapy groups (n = 37). The t tests evaluating the change from baseline to 5 years comparing intensive versus moderate therapy revealed no statistical difference (Table 4).

Figure 7 shows the mean creatinine clearance and log UAE for the patients randomized to nisoldipine (n = 231) versus enalapril (n = 234) during the follow-up period. Neither the mean nor the change in creatinine clearances was different between the two therapy groups. Figure 7 presents lower mean log UAE values at 12, 18, 24, 36, and 42 months for patients randomized to enalapril versus nisoldipine (P < 0.05). This difference in the mean of log UAE was significant up to 3.5 years. In analyses stratified by level of intensity of blood pressure reduction, there was no difference in the change in creatinine clearance and log UAE between those randomized to nisoldipine versus enalapril (data not shown). Figure 8 shows the mean creatinine clearances for those patients starting with normo- and microalbuminuria. There was no difference between those randomized to nisoldipine versus enalapril. The mean creatinine clearances for patients with overt albuminuria are 74.9 ± 4.9 at baseline to 53.3 ml · min^–1· 1.73 m^–2 at 5 years for the nisoldipine group and 77.2 ± 4.9 at baseline to 56.5 ± 5.5 ml · min^–1· 1.73 m^–2 at 5 years for the enalapril group. These decrements in creatinine clearance were not statistically different.

Figure 7—Mean creatinine clearance and log UAE according to nisoldipine versus enalapril therapy. The number of patients completing the creatinine clearance measurements at each time period is listed on the bottom. *The t tests demonstrate a difference in the mean of log UAE at 1, 1.5, 2, 3, and 3.5 years (P < 0.05).

Figure 8—Mean creatinine clearance according to nisoldipine versus enalapril therapy for patients with normoalbuminuria and microalbuminuria at baseline. The number of patients completing the creatinine clearance measurements at each time period is listed on the bottom. The t tests evaluating change from baseline at each time interval reveals no significant difference between the therapies.

Retinopathy
During the follow-up period, 30% of patients randomized to intensive therapy versus 34% of patients randomized to moderate therapy progressed by three steps or more at 5 years (P = 0.42). Using two-step progression, 39% of patients randomized to intensive therapy versus 46% of patients randomized to moderate therapy progressed (P = 0.21).

During the follow-up period, 31% of patients randomized to nisoldipine versus 33% of patients randomized to enalapril progressed by three steps or more at 5 years (P = 0.66). Using two-step progression, 40% of patients randomized to enalapril versus 46% of patients randomized to nisoldipine progressed (P = 0.30).

Neuropathy
During the follow-up period, 40% of patients randomized to intensive therapy versus 31% of patients randomized to moderate therapy had progression of neuropathy at 5 years (P = 0.079). Subanalyses of autonomic neuropathy revealed that 18% of patients in the intensive therapy group developed autonomic neuropathy versus 17% in the moderate therapy group (NS).

During the follow-up period, 36% of patients randomized to nisoldipine versus 36% of patients randomized to enalapril had progression of neuropathy at 5 years (P = 0.99). Subanalyses of autonomic neuropathy revealed that 18% of patients in the nisoldipine group developed autonomic neuropathy versus 17% in the enalapril group (NS).

Cardiovascular events and deaths
During the follow-up period, the patients randomized to intensive therapy had a lower incidence of all-cause mortality when compared to moderate therapy, 5.5 vs. 10.7%, P = 0.037. Subgroup analyses, however, did not reveal a statistically sugnificant difference in MI, cerebrovascular events, or congestive heart failure to account for this difference in all-cause mortality.

CONCLUSIONS — Nearly 40% of patients diagnosed with type 2 diabetes have coexisting hypertension (35). In this regard, hypertension contributes to the presence of diabetic complications including nephropathy, retinopathy, neuropathy, and CVD (2,8,36,37). Diabetes is the leading cause of end-stage renal disease in the U.S., with type 2 diabetes accounting for >65% of the cases of diabetic nephropathy (38). The ABCD Trial is a prospective randomized clinical trial designed to compare the effects of different intensities of blood pressure control and the use of nisoldipine versus enalapril on renal function in hypertensive type 2 diabetic patients. The current article demonstrates that intensive (mean 132/78 mmHg) versus moderate (mean 138/86 mmHg) blood pressure control had no differential effect on creatinine clearance in the hypertensive cohort of the ABCD Trial over a >5-year follow-up period. In addition, there was no difference between patients randomized to nisoldipine versus enalapril with regard to the creatinine clearance.

With both intensive and moderate interventions, creatinine clearance remained relatively stable over the 5-year follow-up period, with a small decline in creatinine clearance occurring within the first year of treatment when compared with the last 4 years. In subgroup analyses, creatinine clearance after 1 year stabilized in patients with normo- and microalbuminuria at baseline. In contrast, patients with overt albuminuria at baseline demonstrated a steady decline in creatinine clearance throughout the follow-up period of 5–6 ml · min^–1· 1.73 m^–2 per year, whether they were in the intensive or moderate treatment group. This overall rate of decline for the ABCD Trial patients with overt albuminuria of 5–6 ml · min^–1· 1.73 m^–2 is similar to that reported by Flemming et al. (39) in a 42-month follow-up period of hypertensive type 2 diabetic subjects with overt albuminuria and considerably less than the 10–12 ml · min^–1· year^–1 observed without treatment of hypertension (40).

More recently, the UKPDS demonstrated that tight blood pressure control (mean 144/82 mmHg) versus less tight control (mean 154/87 mmHg) resulted in less diabetes-related deaths, cerebral vascular accidents, and combined microvascular complications (16). When evaluating the effects on renal function in the UKPDS, tight blood pressure control resulted in a lower urinary albumin concentration, but this difference was not apparent after year 6. The blood pressure levels attained in the ABCD Trial for moderate therapy (138/86 mmHg) were similar to the mean blood pressure in the tight blood pressure control group for the UKPDS. On the other hand, the intensive treatment group in the ABCD Trial evaluated blood pressures below those in the UKPDS. This intensive level of blood pressure control (mean 132/78 mmHg) appeared to be quite safe in hypertensive type 2 diabetic patients without any evidence of a "J curve." In the JNC-VI report, it was proposed that patients with diabetes should have a blood pressure goal <130/85 mmHg (14). The results of the intensive treatment group in the ABCD Trial are compatible with this recommendation and appear to stabilize renal function if initiated before the presence of overt albuminuria (>300 mg/24 h).

Although the presence of microalbuminuria in type 1 diabetes has been a clear indicator of inevitable renal failure if interventions are not performed, the role in type 2 diabetic nephropathy is less clear. Mogensen (41) had originally demonstrated that only 22% of type 2 diabetic patients with microalbuminuria aged 50–75 years developed proteinuria over a 9-year follow-up period. Later studies in younger type 2 diabetic subjects suggest that the development of overt nephropathy from microalbuminuria reaches 40% (42,43) but is still much less than the 80% demonstrated in type 1 diabetic subjects. In the present study, ~20% of the patients advanced from normoalbuminuria to microalbuminuria and from microalbuminuria to overt albuminuria over 5 years. There was however no difference between intensive versus moderate blood pressure control. The absence of a difference between the intensive versus moderate blood pressure control group suggests that a level of blood pressure may have been reached in the moderate group, whereby a further reduction exerts no additional benefit. Alternatively, it cannot be excluded that a larger group of patients and/or a longer follow-up may demonstrate a more beneficial effect in the intensive therapy group.

The present study demonstrated no statistical difference between the use of nisoldipine, a long-acting CCB, versus enalapril, an ACE inhibitor, on diabetic nephropathy, as measured by creatinine clearance and the log UAE over a 5-year follow-up period. However, an initial advantage was observed with enalapril on the log UAE in the first 36 months. The percentage of patients advancing from normo- to microalbuminuria and from microalbuminuria to overt albuminuria was similar for both groups. Previous studies have demonstrated the efficacy of ACE inhibition in diabetic nephropathy in both type 1 and type 2 diabetic subjects (39,44–48). More recently, Ravid et al. (48) demonstrated that use of an ACE inhibitor versus a placebo attenuated the decline in renal function and reduced the extent of albuminuria in normotensive type 2 diabetic patients with normoalbuminuria over a 6-year follow-up period.

As opposed to ACE inhibitors, the use of CCBs for diabetic nephropathy has been less certain. Studies comparing the use of ACE inhibitors to CCBs have involved smaller study populations with follow-up periods often <2 years (45–47,49–51). For the most part, the results from these studies have suggested that use of an ACE inhibitor may be more efficacious than a CCB based on UAE rates but without demonstrating an advantage on glomerular filtration rates. The present study demonstrated a similar advantage of the ACE inhibitor on UAE over the first 3.5 years of the study. There was no difference in creatinine clearance between enalapril and nisoldipine in either the intensive or moderate treatment group. The number of patients who eventually were off study medication at the end of the present study is, however, a caveat.

Earlier studies have suggested that there is a positive relationship between hypertension and the incidence or progression of diabetic retinopathy (8,52–54). In the present study, however, we did not demonstrate a significant difference on the progression of diabetic retinopathy between intensive and moderate blood pressure control or between the use of a CCB versus an ACE inhibitor over the 5-year follow-up. However, the larger UKPDS demonstrated that over a 9-year follow-up, average blood pressure control of 144/82 mmHg versus less control at 154/87 mmHg led to a decreased risk in the progression of retinopathy. In the ABCD Trial, poor glycemic control may have contributed to the progression of the retinopathy. It has been clearly demonstrated that tight glycemic control slows the progression of diabetic retinopathy in both type 1 (55,56) and type 2 (57) diabetic patients.

Of all the complications associated with diabetes, diabetic neuropathy is the most poorly defined, but may be the most common. Cross-sectional studies suggest a relationship between hypertension and the presence of neuropathy (58). Interventional studies with regard to progression of neuropathy have involved glycemic control (55), aldose reductase inhibitors (59), and -lipoic acid (60), but not antihypertensive therapy. In the present study, no differential effects on the progression of neuropathy were observed between intensive and moderate blood pressure therapy or between the CCB and ACE inhibitor. Intensive versus moderate blood pressure control, however, demonstrated a decrease in all-cause mortality; inadequate statistical power did not allow distinguishing between cardiovascular versus noncardiovascular causes.

In summary, the ABCD Trial suggests that creatinine clearance in hypertensive type 2 diabetic patients can be stabilized over 5 years with blood pressures maintained 132/78–138/86 mmHg if therapy is initiated before the onset of overt albuminuria. This supports the JNC-VI recommendation of <130/85 mmHg for diabetic patients. These effects are independent of the use of nisoldipine or enalapril as the initial antihypertensive medication. Once diabetic nephropathy occurred (defined as >200 µg/min [>300 mg/day] of albuminuria), blood pressure control did not totally prevent loss of renal function, which continued at a rate of 5–6 ml · min^–1· 1.73 m^–2 per year. In the current article, we also observed no difference between intensive versus moderate blood pressure control and enalapril versus nisoldipine with regard to the progression of diabetic retinopathy and neuropathy over 5 years. Although the current article demonstrates no difference between the use of a CCB versus an ACE inhibitor with regard to microvascular complications, the use of an ACE inhibitor as the initial antihypertensive medication perhaps should be preferred because of its possible advantage in macrovascular complications (20). Although in need of further study, the intensive blood pressure control group demonstrated a decrease in all-cause mortality.

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From the Department of Medicine (R.O.E.), Division of General Internal Medicine, Colorado Prevention Center and the University of Colorado Health Sciences Center, Denver Health; the Department of Medicine (B.W.J., N.G., R.W.S.), Division of Renal Diseases and Hypertension; and the Department of Biostatistics (B.W.J.), Colorado Prevention Center, Denver, Colorado.

Address correspondence and reprint requests to Robert W. Schrier, MD, Division of Renal Diseases and Hypertension, Department of Medicine, 4200 E. Ninth Ave., #B178, Denver, CO 80262. E-mail: robert.schrier@uchsc.edu.

Received for publication 9 July 1999 and accepted in revised form 7 December 1999.

Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; CCB, calcium channel blocker; CVD, cardiovascular disease; DSMC, Data Safety Monitoring Committee; ETDRS, Early Treatment Diabetic Retinopathy Study; JNC-VI, the Sixth Report of the Joint National Committee; UAE, urinary albumin excretion; UKPDS, U.K. Prospective Diabetes Study.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Aventis Pharma.

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