OBJECTIVE—The Captopril Prevention Project (CAPPP) evaluated the effects of an ACE inhibitor–based therapeutic regimen on cardiovascular mortality and morbidity in hypertension. One planned subanalysis of the CAPPP was to evaluate the outcome in the diabetic patient group.

RESEARCH DESIGN AND METHODS—In the CAPPP, 572 (4.9% of 10,985 hypertensive patients) had diabetes at baseline and were studied according to a prospective, randomized, open, blinded, end point trial design. Patients aged 25–66 years with diastolic blood pressure ≥100 mmHg were included and randomized to receive either captopril or conventional antihypertensive treatment (diuretics and/or β-blockers).

RESULTS—The primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was markedly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018). Specifically, cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084), and no difference was observed between the study groups for stroke (RR = 1.02; P = 0.96). Myocardial infarctions were less frequent in the captopril group than in the conventional therapy group (RR = 0.34; P = 0.002). Furthermore, total mortality was lower in the captopril as compared with the conventional therapy group (RR = 0.54; P = 0.034). Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor–based therapy.

CONCLUSIONS—Captopril is superior to a diuretic/β-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients, especially in those with metabolic decompensation.

Cardiovascular complications represent the major burden of death and disease in patients with diabetes (1,2,3,4,5). Hypertension is a common finding in patients with type 2 diabetes; when present, it is an ominous sign that doubles the already elevated risk of future cardiovascular events (2,3). The results from the recent U.K. Prospective Diabetes Study (UKPDS) Hypertension study (6,7) and the Hypertension Optimal Treatment (HOT) trial (8) demonstrated that aggressive lowering of diastolic blood pressure in diabetic patients to levels <85 and <80 mmHg, respectively, was accompanied by reductions of macrovascular events by about one-third and one-half, respectively. In addition, results from the Systolic Hypertension in the Elderly Program (SHEP) (9) and Systolic Hypertension in Europe (Syst-Eur) trials (10) favored the aggressive antihypertensive treatment of diabetic patients with isolated systolic hypertension.

The choice of antihypertensive agents in diabetic patients without renal impairment has been a matter of controversy. In particular, ACE inhibitors have favorable metabolic, renal, cardiovascular, and quality-of-life effects as compared with other regimens (11,12,13,14,15,16,17). Therefore, ACE inhibitors may be considered as first-line agents in hypertensive diabetic patients. The 1999 Guidelines for the Management of Hypertension, issued by the World Health Organization (WHO) and the International Society of Hypertension, recommended ACE inhibitors, along with diuretics, β-blocking agents, calcium-channel blockers, and angiotensin receptor II antagonists, as suitable first-line agents for diabetic patients (18). However, β-blocking agents or diuretics are preferred as initial therapy in the absence of renal disease according to the recommendations given by the Sixth Joint National Committee in the U.S. (19).

What is the current evidence of ACE inhibitor use in essential hypertension treatment in diabetic patients? The results from the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (20), comprised of 470 patients, showed higher incidence of fatal and nonfatal myocardial infarction in the group assigned to calcium-channel blocker (nisoldipine) treatment than in those assigned to an ACE inhibitor (enalapril). However, the results were based on only 30 incident cases; furthermore, myocardial infarction was a secondary end point in the trial. Similarly, the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) (21) showed lower incidence of acute myocardial infaction and stroke as well as a lower rate of hospitalization due to angina pectoris in the group randomized to fosinopril compared with the group assigned to amlodipine. The UKPDS–hypertension tight control arm also provided a comparison (7) between two regimens, captopril 25–50 mg twice daily and atenolol 50–100 mg daily. The incidence of diabetic complications was reduced to a similar extent in the two groups during follow-up, suggesting that blood pressure reduction in itself may be more important than the type of antihypertensive treatment used. However, compliance with the drug regimen in the UKPDS was superior in the captopril group compared with the atenolol group. In addition, the increase in body weight was approximately twice as high in subjects receiving β-blockers compared with patients receiving an ACE inhibitor.

The Captopril Prevention Project (CAPPP) was the first intervention study (22,23) in hypertension to evaluate the effects of an ACE inhibitor–based therapeutic regimen on cardiovascular morbidity and mortality. In the present study, cardiovascular mortality and morbidity in the diabetic subpopulation is further analyzed.

The CAPPP was conducted at 536 health centers in Sweden and Finland using the PROBE (Prospective Randomized Open Blinded Endpoint) study design (22,24), which has great similarity to routine clinical practice. Patients were treated and followed for an average of 6.1 years (23). Male and female patients with treated or untreated primary hypertension, aged 25–66 years, were included if their untreated diastolic blood pressure was ≥100 mmHg on two different occasions. Patients with secondary hypertension, serum creatinine >150 μmol/l, and indications requiring β-blockade treatment were excluded. Eligible patients were randomized to receive either a captopril-based regimen or conventional antihypertensive treatment (diuretics and/or β-blockers).

The treatment goal was a supine diastolic blood pressure ≤90 mmHg. To reach this goal, the dose could be increased to 100 mg daily (once or twice daily) in the captopril-treated group; if necessary, a diuretic could be added. In the conventionally treated group, an optimal dose of a β-blocker or a diuretic was used. The investigators were free to choose the agents, and in a second step, the diuretic and the β-blocker could be combined. As a last step, a calcium-channel blocker could be added in both treatment groups.

The primary end point was the combination of fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths. Events were evaluated by an independent and blinded end point committee before being accepted. Secondary end points were new or deteriorated ischemic heart disease (IHD) and congestive heart failure (CHF), atrial fibrillation, diabetes, transient ischemic attacks, and noncardiovascular deaths as previously defined (22,23).

The diagnosis of diabetes was made according to WHO criteria (25) and required at least two abnormal fasting glucose values that were unequivocal (i.e., between 5.5 and 6.7 mmol/l). If they were not unequivocal, diagnosis was confirmed by an oral glucose tolerance test.

The diabetic patients were, for the most part, treated with diet and/or oral hypoglycemic agents at baseline (Table 1), and thus they had type 2 diabetes. The CAPPP study was approved by ethics committees at participating centers in Sweden and Finland.

Statistics

Analysis was by intention to treat. Cox regression analyses were performed, with time since randomization as the nonparametrically modeled time variable; age at randomization was therefore introduced as a covariate. Further covariates used were sex and systolic blood pressure at randomization. Both systolic blood pressure at randomization and previously untreated patients as well as their product were introduced into the model (23). All computations were performed in the commercial software Stata. P < 0.05 (two-sided) was considered statistically significant.

Among the 10,985 patients in the CAPPP, there were 309 patients with diabetes in the captopril group and 263 in the conventional therapy group. These 572 patients provided 3,445 patient-years, and only one of them was lost to follow-up. Blood pressure at baseline was similar in the captopril compared with the conventional therapy group (163.6/97.1 vs. 163.3/97.3 mmHg). The baseline characteristics were comparable between the two study groups (Table 1). Blood pressure levels during the study are shown in Fig. 1. If the in-study blood pressure for every diabetic patient is defined as the average of all blood pressure recordings from 12 months onwards, then these in-study blood pressures were somewhat higher in the captopril than in the conventional group (155.5/89.0 mmHg; P = 0.091 vs. 153.5/88.0 mmHg; P = 0.040).

In diabetic patients, the incidence of the primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was significantly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018) (Tables 2 and 3 and Fig. 2). When the events comprising the primary end point were analyzed separately, the following results were obtained: 1) cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084) (Table 2); 2) fatal and nonfatal strokes did not differ between the study groups (RR = 1.02; P = 0.959) (Table 2); and 3) fatal and nonfatal myocardial infarctions were markedly less frequent in the captopril than in the conventional therapy group (RR = 0.34; P = 0.002) (Table 2).

Analyses of secondary events showed that 1) total mortality was lower in the captopril than in the conventional therapy group (RR = 0.54; P = 0.034) (Table 2), and 2) all cardiac events (fatal and nonfatal myocardial infarction, other cardiovascular deaths, and sudden deaths as well as IHD, CHF, and atrial fibrillation) were lower in the captopril than in the conventional therapy group (RR = 0.67; P = 0.029) (Table 2).

In addition, we investigated whether the observed benefits of ACE inhibitor–based therapy in diabetic patients could be related to baseline clinical and metabolic characteristics. Thus, the effects of captopril versus conventional treatment on the RRs of the primary end point were further analyzed in various subgroups. These were sex and dichotomized continuous variables, including BMI, fasting glucose, blood pressure, and serum cholesterol, as well as HDL cholesterol and serum triglycerides which were dichotomized at their median values (Table 3). The benefits of captopril therapy were more evident in male diabetic patients (P = 0.004) and in those with poor glycemic control (P = 0.033) and tended to be more pronounced in those with elevated serum cholesterol (P = 0.052) and lowered HDL cholesterol (P = 0.052). In these analyses, P values were adjusted for the effects of age, sex, previously untreated patients, and systolic blood pressure.

The incidence of new-onset diabetes in an originally nondiabetic study population was 337 in the captopril group and 380 in the conventional group (RR 0.79; P = 0.007) (23).

In regard to the effects on cardiovascular morbidity and mortality, the CAPPP study (23) was the first intervention trial in hypertensive patients to compare an ACE inhibitor–based therapy with conventional antihypertensive therapy that was based on diuretics and/or β-blockers. For the entire study population, diabetic and nondiabetic subjects combined, both regimens were equally effective in preventing the primary end point. However, the effects of the two regimens in the diabetic subpopulation showed a clear difference in the risk of developing a primary end point in favor of a captopril-based regimen. Importantly, captopril treatment in the diabetic subpopulation reduced fatal cardiovascular events by about one-half. However, as a subgroup analysis, the data should be interpreted with caution.

At baseline, blood pressure levels and other characteristics were comparable between the captopril and conventional groups. During the study, the achieved blood pressure levels were, if anything, somewhat higher in the captopril than in the conventional regimen; therefore, the favorable outcomes are evidently not explained by differences in blood pressure reductions.

At first sight, these findings may seem to deviate from those of the UKPDS (7), which showed no advantage for captopril over atenolol in reducing the risk of macro- and microvascular diabetic complications. The divergent findings may be explained to a great extent by the fact that the blood pressure treatment goal was lower in the UKPDS (<150/85 mmHg) than in the CAPPP study (<90 mmHg). These findings from the UKPDS suggest that blood pressure lowering may be more important per se than the choice of antihypertensive agent, although captopril was better tolerated by most patients (7). Because the effective lowering of blood pressure in the UKPDS was highly beneficial in diabetic patients, this confirms the observations in the HOT study in which the excess risk of having diabetes was almost nullified in patients whose diastolic blood pressure was reduced to ∼80 mmHg (8). Furthermore, the diabetic patients recruited in the UKPDS generally had milder disturbances in glucose metabolism (inclusion criteria: UKPDS, fasting plasma glucose >6.0 mmol/l; WHO, plasma glucose ≥7.8 mmol/l corresponding to blood glucose ≥6.7 mmol/l). In addition, patients with symptomatic cardiovascular disease were not included in the UKPDS; therefore, the patients in that study were probably at lower risk than the diabetic patients in the CAPPP study.

The results from the analysis of diabetic patients in the CAPPP study further suggest that the choice of antihypertensive drug regimen may be of importance when there is metabolic decompensation, e.g., in those patients with poor glycemic control and perhaps in those with more unfavorable lipid abnormalities. Thus, these results support those of the Heart Outcomes Prevention Evaluation (HOPE) study (26,27), which showed that subjects with multiple risk factors are likely to benefit from ACE inhibitor–based therapy, because the protective effect is well beyond that obtained by blood pressure reduction per se. The favorable effects of ACE inhibitor–based therapy may be a result of the improvement of whole-body glucose uptake observed with captopril treatment during euglycemic clamp measurements (11). There are also a variety of other disturbances in diabetic patients that are improved by ACE inhibition, e.g., attenuation of sympathetic nerve activity (28), enhancement of nitric oxide formation (29), improvement of endothelial dysfunction (30), improvement in coronary reserve (31), and even the direct inhibition of the atherosclerosis process, as suggested by animal experiments (32).

In conclusion, analysis of the outcome of the diabetic patient group in the CAPPP showed that the ACE inhibitor is an obvious first-choice drug for hypertensive patients with diabetes, especially when there is metabolic decompensation. However, because elevated blood pressure levels should be aggressively treated in diabetic patients, a multiple drug regimen is commonly required to achieve optimal treatment targets.

CAPPP study investigators

Steering committee: Lennart Hansson, Jan-Erik Björck, Björn Dahlöf, Ulf de Faire, Thomas Hedner, Bengt E. Karlberg, Jan Lanke, Lars H. Lindholm, Kimmo Luomanmäki, Claes Mörlin, Leo Niskanen, P. O. Wester. End point committee: Gottfried Härtel, Pentti Siltanen, Karl Swedberg, Andreas Terent. End point secretariat, Gothenburg: Anita Holmner. Safety committee: Leif Erhardt, Markku Kupari, Thomas Thulin, Pär-Ola Bendahl (statistician). Data management, Lund: Björn Slaug. Coordinators: Sweden: Per-Olof Andersson, Johan Asplund, Anders Dahlqvist, Björn Fagerberg, Göran Frithz, Bengt-Göran Hansson, Anders Hägg, Svend Aage Jonsen, Thomas Kahan, Bo Carlberg, Bo Erik Kristensson, Jörgen Kuylenstierna, Hans Larsson, Bengt Lindström, Ingrid Mattiasson, Bengt-Hjalmar Möller, Ove R. Nilsson, Håkan Stakeberg, Anders Svensson, Kerstin Tolagen, Leif Weiner, Brage Åström, Jan Östergren; Finland: Aapo Lehtonen, Mauno Lilja, Matti Nikkilä, Juhani Partanen; and all CAPPP investigators (23).

Figure 1—

Blood pressure levels in diabetic patients during the CAPPP study. ♦, Captopril treatment group; •, conventional treatment group.

Figure 1—

Blood pressure levels in diabetic patients during the CAPPP study. ♦, Captopril treatment group; •, conventional treatment group.

Close modal
Figure 2—

Comparison by intervention group of diabetic and nondiabetic patients who remained free from primary end point (fatal or nonfatal stroke, myocardial infarction, or other fatal cardiovascular events) in the CAPPP cohort.

Figure 2—

Comparison by intervention group of diabetic and nondiabetic patients who remained free from primary end point (fatal or nonfatal stroke, myocardial infarction, or other fatal cardiovascular events) in the CAPPP cohort.

Close modal
Table 1—

Baseline characteristics of diabetic patients in CAPPP randomized to captopril or conventional treatment

CaptoprilConventional
n 309 263 
M/F 196/113 158/105 
Age (years) 55.0 (7.6) 55.7 (7.4) 
Weight (kg) 90.4 (16.7) 88.8 (15.9) 
Height (cm) 171.6 (8.9) 171.1 (8.8) 
BMI (kg/m230.8 (5.1) 30.2 (4.6) 
Supine SBP (mmHg) 163.6 (18.8) 163.3 (20.6) 
Supine DBP (mmHg) 97.1 (9.6) 97.3 (10.1) 
Previously untreated 113 99 
Smokers 55 44 
History of myocardial infarction 
History of IHD 10 10 
History of stroke 
Congestive heart failure 
History of cardiovascular complications 33 19 
Albuminuria (Albustix-positivity) 34 (11) 23 (9) 
Serum cholesterol (mmol/l) 6.12 (1.19) 6.29 (1.21) 
HDL cholesterol (mmol/l) 1.12 (0.32) 1.17 (0.39) 
Serum triglycerides (mmol/l) 3.69 (1.92) 3.44 (1.49) 
Fasting blood glucose (mmol/l) 8.7 (2.7) 8.9 (3.0) 
Treatment of diabetes   
 Diet 201 173 
 Oral hypoglycemic drug 97 74 
 Insulin 11 16 
CaptoprilConventional
n 309 263 
M/F 196/113 158/105 
Age (years) 55.0 (7.6) 55.7 (7.4) 
Weight (kg) 90.4 (16.7) 88.8 (15.9) 
Height (cm) 171.6 (8.9) 171.1 (8.8) 
BMI (kg/m230.8 (5.1) 30.2 (4.6) 
Supine SBP (mmHg) 163.6 (18.8) 163.3 (20.6) 
Supine DBP (mmHg) 97.1 (9.6) 97.3 (10.1) 
Previously untreated 113 99 
Smokers 55 44 
History of myocardial infarction 
History of IHD 10 10 
History of stroke 
Congestive heart failure 
History of cardiovascular complications 33 19 
Albuminuria (Albustix-positivity) 34 (11) 23 (9) 
Serum cholesterol (mmol/l) 6.12 (1.19) 6.29 (1.21) 
HDL cholesterol (mmol/l) 1.12 (0.32) 1.17 (0.39) 
Serum triglycerides (mmol/l) 3.69 (1.92) 3.44 (1.49) 
Fasting blood glucose (mmol/l) 8.7 (2.7) 8.9 (3.0) 
Treatment of diabetes   
 Diet 201 173 
 Oral hypoglycemic drug 97 74 
 Insulin 11 16 

Data are mean (SD) or n. DBP, diastolic blood pressure; SBP, systolic blood pressure.

Table 2—

Number of patients with events during follow-up and RR for diabetic patients in the captopril vs. conventional therapy groups

CaptoprilConventionalRR* (95% CI)P
Primary end point 35 46 0.59 (0.38–0.91) 0.018 
Fatal myocardial infarction   
Fatal stroke   
Other cardiovascular deaths   
Sudden death   
Atrial fibrillation 12   
CHF 11 17   
Other fatal events 11 15   
All myocardial infarction 12 27 0.34 (0.17–0.67) 0.002 
All stroke 23 19 1.02 (0.55–1.87) 0.96 
All fatal events 20 34   
All cardiac events 54 63 0.67 (0.46–0.96) 0.029 
Fatal cardiovascular events   0.48 (0.21–1.10) 0.084 
Total mortality   0.54 (0.31–0.95) 0.034 
CaptoprilConventionalRR* (95% CI)P
Primary end point 35 46 0.59 (0.38–0.91) 0.018 
Fatal myocardial infarction   
Fatal stroke   
Other cardiovascular deaths   
Sudden death   
Atrial fibrillation 12   
CHF 11 17   
Other fatal events 11 15   
All myocardial infarction 12 27 0.34 (0.17–0.67) 0.002 
All stroke 23 19 1.02 (0.55–1.87) 0.96 
All fatal events 20 34   
All cardiac events 54 63 0.67 (0.46–0.96) 0.029 
Fatal cardiovascular events   0.48 (0.21–1.10) 0.084 
Total mortality   0.54 (0.31–0.95) 0.034 
*

Adjusted for age, sex, systolic blood pressure, and previously untreated/treated patients. Primary end point refers to fatal or nonfatal stroke, myocardial infarction, or other cardiovascular death.

Table 3—

Effect of captopril treatment on the primary end points in diabetic patients by sex, baseline BMI, fasting glucose, systolic and diastolic blood pressure, and serum lipids

RR* (95% CI) (Captopril vs. conventional)P
Sex   
 M 0.47 (0.28–0.79) 0.004 
 F 1.08 (0.45–2.59) 0.86 
BMI (kg/m2  
 < median (29.9) 0.56 (0.30–1.04) 0.068 
 ≥ median 0.70 (0.36–1.36) 0.29 
Fasting glucose (mmol/l)   
 < median (8.1) 0.85 (0.35–2.06) 0.73 
 ≥ median 0.49 (0.25–0.94) 0.033 
Systolic blood pressure (mmHg)   
 < median (160 or, if untreated, 163) 0.64 (0.34–1.18) 0.15 
 ≥ median 0.54 (0.29–1.02) 0.054 
Diastolic blood pressure (mmHg)   
 < median (95 or, if untreated, 100) 0.71 (0.40–1.27) 0.24 
 ≥ median 0.47 (0.24–0.95) 0.036 
Serum cholesterol (mmol/l)   
 < median (6.03) 0.66 (0.36–1.24) 0.20 
 ≥ median 0.52 (0.26–1.01) 0.052 
HDL cholesterol (mmol/l)   
 < median (1.09) 0.42 (0.17–1.01) 0.052 
 ≥ median 0.52 (0.17–1.56) 0.24 
Serum triglycerides (mmol/l)   
 < median (3.57) 0.54 (0.18–1.63) 0.29 
 ≥ median 0.79 (0.37–1.72) 0.56 
RR* (95% CI) (Captopril vs. conventional)P
Sex   
 M 0.47 (0.28–0.79) 0.004 
 F 1.08 (0.45–2.59) 0.86 
BMI (kg/m2  
 < median (29.9) 0.56 (0.30–1.04) 0.068 
 ≥ median 0.70 (0.36–1.36) 0.29 
Fasting glucose (mmol/l)   
 < median (8.1) 0.85 (0.35–2.06) 0.73 
 ≥ median 0.49 (0.25–0.94) 0.033 
Systolic blood pressure (mmHg)   
 < median (160 or, if untreated, 163) 0.64 (0.34–1.18) 0.15 
 ≥ median 0.54 (0.29–1.02) 0.054 
Diastolic blood pressure (mmHg)   
 < median (95 or, if untreated, 100) 0.71 (0.40–1.27) 0.24 
 ≥ median 0.47 (0.24–0.95) 0.036 
Serum cholesterol (mmol/l)   
 < median (6.03) 0.66 (0.36–1.24) 0.20 
 ≥ median 0.52 (0.26–1.01) 0.052 
HDL cholesterol (mmol/l)   
 < median (1.09) 0.42 (0.17–1.01) 0.052 
 ≥ median 0.52 (0.17–1.56) 0.24 
Serum triglycerides (mmol/l)   
 < median (3.57) 0.54 (0.18–1.63) 0.29 
 ≥ median 0.79 (0.37–1.72) 0.56 
*

RRs are adjusted for age, sex, baseline systolic blood pressure, and previously untreated/treated patients when applicable.

This study was supported by a project grant from Bristol-Myers Squibb.

1.
Garcia MJ, McNamara PM, Gordon T, Kannel WB: Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up.
Diabetes
23
:
105
–111,
1974
2.
Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
Diabetes Care
16
:
434
–444,
1993
3.
The Hypertension in Diabetes Study Group: Hypertension in Diabetes Study (HDS). II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients.
J Hypertens
11
:
319
–325,
1993
4.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med
339
:
229
–234,
1998
5.
Niskanen L, Turpeinen A, Penttilä I, Uusitupa MI: Hyperglycemia and compositional lipopoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis.
Diabetes Care
21
:
1861
–1869,
1998
6.
UK Prospective Diabetes Study Group: Tight blood pressure and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ
317
:
703
–713,
1998
7.
UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.
BMJ
317
:
713
–720,
1998
8.
Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfelt D, Julius S, Menard J, Rahr H, Wedel H, Westerling S, for the HOT study group: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
Lancet
351
:
1755
–1762,
1998
9.
Curb JD, Pressel SL, Cutler J, Savage PJ, Applegate WB, Black H, Camel G, Davis B, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-based antihypertensive treatment on cardiovascular risk in older diabetic patients with isolated systolic hypertension.
JAMA
276
:
1886
–1892,
1996
10.
Tuomilehto J, Rastenyte D, Birkenhäger WH, Thijs L, Antikainen R, Bulpitt CJ, Fletcher AE, .Forette F, Goldhaber A, Palatini P, Sarti C, Fagard R, for the Systolic Hypertension in Europe Trial investigators: Effect of calcium-channel blockage in older patients with diabetes and systolic hypertension.
N Engl J Med
340
:
677
–684,
1999
11.
Pollare T, Lithell H, Berne C: A comparison of the effect of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension.
N Engl J Med
321
:
868
–873,
1989
12.
Dahlöf B, Pennert K, Hansson L: Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies.
Am J Hypertens
5
:
95
–110,
1992
13.
Schmieder RE, Marttus P, Klingbeil A: Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies.
JAMA
275
:
1507
–1513,
1996
14.
Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltma EM, Goldman S, Flaker GC, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement investigators.
N Engl J Med
327
:
669
–677,
1992
15.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative study group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
N Engl J Med
329
:
1456
–1462,
1993
16.
Giatras I, Lau J, Levey AS, for the Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease study group: Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials.
Ann Intern Med
127
:
346
–355,
1997
17.
Croogh SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, Klerman GL, Williams GH: The effects of antihypertensive therapy on the quality of life.
N Engl J Med
314
:
1657
–1664,
1984
18.
Guidelines Subcommittee: World Health Organization/International Society of Hypertension: guidelines for the management of hypertension.
J Hypertens
17
:
151
–183,
1999
19.
The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).
Arch Intern Med
157
:
2413
–2446,
1997
20.
Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension.
N Engl J Med
338
:
645
–652,
1998
21.
Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F: Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM.
Diabetes Care
21
:
597
–603,
1998
22.
Hansson L, Hedner T, Lindholm L, Niklason A, Luomanmäki K, Niskanen L, Lanke J, Dahlöf B, de Faire U, Morlin C, Karlberg BE, Wester PO, Björck JE. for the CAPPP Study Group: The Captopril Prevention Project (CAPPP) in hypertension. Baseline data and current status.
Blood Pres
sure
6
:
365
–367,
1997
23.
Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmäki K, Dahlöf B, de Faire U, Mörlin C, Karlberg BE, Wester PO, Björk JE, for the Captopril Prevention Project (CAPPP) study group: Effect of angiotensin-converting-enzyme inhibition compared with conventional morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
Lancet
353
:
611
–616,
1999
24.
Hansson L, Hedner T, Dahlöf B: Prospective Randomized Open Blinded Endpoint (PROBE) study: a novel design for intervention trials.
Blood Pressure
1
:
113
–119,
1992
25.
World Health Organization: WHO Expert Committee on Diabetes Mellitus: Geneva, World Health Org., 1985 (Tech. Rep. Ser., no. 727)
26.
The Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
N Engl J Med
342
:
145
–153,
2000
27.
Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.
Lancet
355
:
253
–259,
2000
28.
Giannattasio C, Cattaneo BM, Omboni S, Seravalle G, Bolla G, Turolo L, Morganti A, Grassi G, Zanchetti A, Mancia G: Sympathomoderating influence of benazepril in essential hypertension.
J Hypertens
10
:
373
–378,
1992
29.
Hornig B, Kohler C, Drexler H: Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans.
Circulation
95
:
1115
–1118,
1997
30.
Mancini GBJ, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra II, Luscher TF, Klibaner MI,Haber IIE, Uprichard AC, Pepine CJ, Pitt B: Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease.
Circulation
94
:
258
–265,
1996
31.
Motz W, Strauer BE: Improvement of coronary flow reserve after long-term therapy with enalapril.
Hypertension
27
:
1031
–1038,
1996
32.
Schuh JR, Blehm DJ, Frierdich GE, McMahon EG, Blaine EH: Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.
J Clin Invest
91
:
1453
–1458,
1993

Address correspondence and reprint requests to Leo Niskanen, MD, Associate Professor, Department of Medicine, University of Kuopio, Box 1777, FIN-70211 Kuopio, Finland. E-mail: leo.niskanen@kuh.fi.

Received for publication 24 March 2001 and accepted in revised form 4 September 2001.

The names of CAPPP investigators appear in an appendix at the end of this article.

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