Selection of antihypertensive drug in diabetes mellitus

ACE inhibitors, nondihydropyridine CCBs, TDs, and bBs reduced CV complications in patients who had diabetes and hypertension in several long-term, large, RCTs (Tables 3 and 4). Limited data is available with direct comparisons of various drugs in diabetic, hypertensive patients (Table 5).

There was no convincing evidence from several large RCTs (eg, CAPPP [26], Swedish Trial in Old Patients with Hypertension 2 [STOP-2] [68], Nordic Diltiazem [NORDIL] study [69], and Intervention as a Goal in Hypertension Treatment

[INSIGHT] [70]) that newer agents, such as ACE inhibitors and CCBs, are better than diuretics and bBs in reducing CV events in treating hypertension in the general population. Because diabetes is an important and independent risk factor for CV morbidity and mortality and because most diabetics die of CV complications [1], subgroup analysis of diabetic, hypertensive patients in these trials revealed that most required multiple drugs for adequate control of their BP.

Angiotensin-converting enzyme inhibitors versus other agents

In the CAPPP trial, diabetic patients who were on captopril had less cardiac mortality and all-cause mortality than did those who were on bBs or TDs [26]. The report did not further divide the impact of captopril over bBs or TDs. However, the STOP-2 did not find any difference in major CV events and total mortality among patients who were randomized to TDs/bBs versus ACE inhibitors versus CCBs [67], although there was a statistically significant reduction in myocardial infarction (MI) in those who were on ACE inhibitors compared with those who received CCBs (see Table 5). The data from CAPPP and STOP-2 are based on post hoc analysis because only a small percentage of participants were diabetic; thus, such analyses may suffer from inherited bias (eg, violation of randomization). In contrast, the UKPDS, ABCD, and FACET trials included only diabetic patients who had hypertension. Results from these three trials seem to be more convincing in favor of ACE inhibitor use in diabetic patients. The UKPDS demonstrated

Table 3

Subgroup analysis of effects of antihypertensive agents on cardiovascular complications in type 2 diabetes in randomized, placebo-controlled trials

N (% of patients who Duration CV MI Stroke Total

Trial had DM-2) Agents (y) eventsa RR RR RR mortality RR

SHEP [40] 4736 (12.3) Chlorthalidone 5 0.66a 0.46c 0.78 0.74

Atenololb

SYST-EUR [14] 4695 (10.5) Nitrendipine 2 0.31c 0.37c,d 0.27c 0.45c

HOPE [30] 9297 (38.5) Ramipril 4.5 0.77c 0.9c 0.69c 0.77c

Relative risks of outcomes for active treatment compared with placebo.

Abbreviations: DM-2, diabetes mellitus type 2; MI, myocardial infarction; RR, relative risk; SYST-EUR, Systolic Hypertension in Europe Trial.

a CV events include myocardial infarction, sudden cardiac death, revascularization, and stroke. b Atenolol was added if chlorthalidone was not effective. c Statistically significant. d For cardiac events.

Table 4

The effect of tight versus less tight blood pressure control on cardiovascular complications in type 2 diabetes in randomized, active-controlled trials

Baseline Achieved

N (% who BP BP Duration CV Total

Table 4

The effect of tight versus less tight blood pressure control on cardiovascular complications in type 2 diabetes in randomized, active-controlled trials

Baseline Achieved

N (% who BP BP Duration CV Total

Trial

had DM)

Agents

(mm Hg)

(mm Hg)

(y)

events

MI

Stroke death

UKPDS [3]

1148 (100)

Captopril or

T 159/94

144/82

9

u

#

u #

atenolol

LT 160/94

154/87

ABCD [67]a

470 (100)

Nisoldipine or

T 156/98

132/78

5.3

NE

NE

NE U

enalapril

LT 154/98

138/86

HOT [52]

18,790 (8.0)

Felodipine

170/105

140/81

3.8

U

#

Abbreviations: #, statistically nonsignificant reduction; ##, statistically significant reduction; LT, less tight; NE, no effect; T, tight.

a Patients were assigned randomly to tight or less tight control groups. Within each group, patients were treated further randomly with nisoldipine or enalapril. The comparison in this table was between moderate and intensive therapy instead of between nisoldipine and enalapril as shown in Table 3.

that the benefit that was achieved with captopril was similar to that of atenolol; however, captopril was only given once or twice daily; this may account partially for its lack of superiority over atenolol. Thirty-six percent of patients who received atenolol and 27% patients who received captopril also received nifedipine to achieve target BP control in the UKPDS [5]. This also might make it difficult to determine the difference between various treatments. ACE inhibitors were superior to dihydropyridine CCBs in randomized head-to-head comparator studies, such as the

ABCD and the FACET trials (see Table 5) [53,54]. Thirty-one percent of patients who received fosinopril received additional amlodipine, whereas fosinopril was added to 26% of patients who received amlodipine in the FACET trial. This may underestimate the benefits of fosinopril. The results of these two trials also raised significant concern regarding the safety of dihydropyridine CCBs in diabetic, hypertensive patients. Generally, it is not recommended that dihydropyridine CCBs be used as initial therapy in diabetic, hypertensive subjects.

Table 5

Head-to-head comparison of antihypertensive agents in randomized, actively-controlled trials in type 2 diabetic patients who had hypertension

N (# who CV Confidence Total

Table 5

Head-to-head comparison of antihypertensive agents in randomized, actively-controlled trials in type 2 diabetic patients who had hypertension

Trial

had DM)

Agents

Years

events Interval) Stroke mortality

UKPDS [3]

1148

Captopril vs

9

Not reported 1.2 (0.82-1.76) 1.12 (0.59-2.12) 1.14 (0.81-1.61)

(1148)

atenolol

ABCD [53]

470

Enalapril vs

5

0.43 (0.25-0.73) 0.18 (0.07-0.48) 0.63 (0.24-1.67) 0.77 (0.36-1.67)

(470)

nisoldipine

FACET [54]

380

Fosinopril vs

2.8

0.49 (0.26-0.95) 0.77 (0.34-1.75) 0.39 (0.12-1.23) 0.81 (0.22-3.02)

(380)

amlodipine

CAPPP [26]

10985

Captopril vs

6.1

0.59 (0.38-0.91) 0.34 (0.17-0.67) 1.02 (0.55-1.88) 0.54 (0.31-0.96)

(572)

diuretics, ßB

STOP-2 [67]

6614

ACE-Is vs

4

0.94 (0.67-1.32) 0.51 (0.28-0.92) 1.16 (0.71-1.91) 1.14 (0.78-1.67)

(466)

CCBsa

STOP-2 [67]

6614

ACE-Is vs

4

0.85 (0.62-1.18) 0.68 (0.37-1.26) 0.88 (0.56-1.40) 0.88 (0.62-1.26)

(488)

diuretics or ßBa

Relative risks compared ACE inhibitors with other agents.

a In the STOP-2 trial, bBs included atenolol, metoprolol, and pindolol; CCBs were felopipine and isradipine; and ACE inhibitors included enalapril and lisinopril.

Calcium-channel blockers versus other agents

Trials that have compared CCBs, diuretics, and bBs are limited. Diltiazem was compared with diuretics and bBs in the NORDIL trial that involved 10,881 hypertensive patients. There was a slight, but statistically significant, decreased incidence of stroke in the group that received diltiazem, despite the fact that the achieved systolic BP was 3 mm Hg higher in that group. Although the study was not designed to compare these three classes of agents independently, the post hoc analysis of 727 participants who had diabetes mellitus did not show any difference in CV-related outcomes between the diltiazem-based therapeutic regimen and a TD or bB regimen [69]. Conversely, more fatal MIs and heart failure were noted in patients who received nifedipine compared with diuretics in the INSIGHT trial [70]. Nevertheless, the total mortality was the same and the subgroup analysis of diabetic patients was not reported. Moreover, the high drop-out rate in the INSIGHT study makes the results difficult to interpret. Furthermore, the STOP-2 trial did not find any difference in major CV events and total mortality among diabetic patients who were randomized to TDs/bBs versus CCB in a post hoc analysis [67]. In summary, although these three trials do not provide an unequivocal answer regarding the selection of the best agent among CCBs, TDs, and bBs in diabetic patients, based on the results of the FACET and the ABCD trials it is well-accepted that dihydropyridine CCBs should not be used as first-line therapy in diabetic, hypertensive patients.

Surrogate markers

Selection of an antihypertensive agent should be based on the effects of the given agent on hard outcomes, such as CV mortality and total mortality, rather than on its metabolic or surrogate effects. For example, despite the unfavorable metabolic effects of TDs or bBs, these drugs are preferred over AAAs based on their long-term morbidity and mortality benefits. The available data (see Table 5) suggest that ACE inhibitors should be the agents of choice in diabetics who have hypertension. Although it usually is considered that bBs should be the first choice in hypertensive diabetics who have CAD, the recent data from the HOPE study suggests that an ACE inhibitor also should be used to achieve maximum cardioprotection. TDs and CCBs can be the add-on agents if the BP is still uncontrolled.

Agents of choice in diabetic patients who have renal failure

ACE inhibitors and ARBs are the only drugs that have been proven to reduce the ESRD and death in diabetic patients who have renal failure. In the landmark study by Lewis et al [71], captopril was able to reduce the rate of end-stage renal failure and death in patients who had type 1 diabetes and hypertension by 50%. The role of ACE inhibitors in patients who have type 2 diabetes and renal failure is not-well defined; only a few, small-scale studies have evaluated their role. Treatment with enalapril slowed down the increase in serum creatinine and stopped the increase in urine albumin excretion in normo-albuminuric [72] and microalbuminuric [73] diabetic patients who did not have hypertension. Because of the small sample size and short-term follow-up period, these studies were unable to evaluate the effectiveness of ACE inhibitors on the development of end-stage renal failure. Also, because the control groups only received placebo, it is not clear if the benefit was due to a BP decreasing effect or the specific effect of ACE inhibitors on kidney function [74]. The data from evaluation of surrogates, such as proteinuria, are, however, convincing. For example, in the SHEP trial, TD therapy slowed the development of proteinuria in diabetic, hypertensive patients [40]. More recently, in the HOPE study [27,30], ramipril had antiproteinuric effect. Comparative data regarding the benefits of various antihyper-tensive drugs are lacking. More recent data in the UKPDS did not substantiate the superiority of captopril over atenolol in regards to proteinuria and renal protection in patients who had type 2 diabetes [3,5].

In contrast, several large-scale RCTs demonstrated the benefit of ARBs in patients who had early- or late-stage diabetic nephropathy and type 2 diabetes [74]. Based on these results, it has been recommended that ARBs, as a class, should be the therapy of choice for most diabetic patients who have microalbuminuria or advanced nephropathy. No head-to-head comparison has been made in any RCT between ACE inhibitors and ARBs in diabetic patients who have nephropathy. Such studies are needed; some investigators believe that ACE inhibitors are overall superior agents for diabetic patients because of their vasculoprotec-tive effects.

ACE inhibitors also were superior to dihy-dropyridine CCBs on CV end points in diabetic patients who did not have kidney failure [53,54]. Based on these facts, it seems reasonable to consider ACE inhibitors as the first-line drug for diabetic, hypertensive patients who have albuminuria.

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