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Angiotensin-converting enzyme inhibitors

Angiotensin-converting-enzyme (ACE) inhibitors are the initial drug choice for patients who have diabetes and hypertension, especially those who have albuminuria. Although initially recommended based on a small set of data, several recent RCTs clearly support the use of ACE inhibitors based on their favorable impact on CV and renal outcomes.

ACE is responsible for the conversion of angiotensin I to angiotensin II, which elevates BP by direct vasoconstriction as well as salt and water retention due to increased aldosterone secretion. ACE inhibitors block production of angiotensin II and degradation of bradykinin, and as a result, decrease the BP [24,25]. ACE

inhibitors also reduce insulin resistance. ACE inhibitors decreased the incidence of new-onset diabetes mellitus in the Captopril Prevention Project (CAPPP) [26] and the Heart Outcomes Prevention Evaluation (HOPE) [27] studies. This is believed to occur secondary to improved insulin sensitivity, which also might result in better glycemic control in diabetic patients [28,29]. No large, randomized, placebo-controlled trial involved only diabetic patients with ACE inhibitors. Nevertheless, the benefit of ACE inhibitors in diabetic patients who had hypertension was well-illustrated in the HOPE trial. In the HOPE [27,30] study, 56% of the subjects were hypertensive and 39% were diabetic. The HOPE study demonstrated that the benefits of ACE inhibitors extend far beyond BP reduction. Although the reduction in mean BP was only 2.4/1.0 mm Hg with ramipril during the 4.5-year study period, there was an impressive 37% risk reduction in death from CV causes and a 24% decrease in all-cause mortality [30]. There also was a 16% decrease in the combined risk of overt nephropathy, dialysis, and laser therapy. These data suggest that ACE inhibitors have additional vasculoprotective and cardioprotective effects. Whether the cardiopro-tective effect is mediated, in part, by reducing insulin resistance is not clear.

Generally, ACE inhibitors are well-tolerated; hyperkalemia (mostly in patients who have renal insufficiency) [31], renal failure (in patients who have bilateral renal artery stenosis), and angio-edema were the most severe, but rarely-reported, adverse effects for the entire class (Table 1). The bradykinin-potentiating effect of ACE inhibitors [32] is responsible for the annoying cough that is secondary to ACE inhibitors and that occurs in up to 10% of patients [33]. There is no evidence that one ACE inhibitor is better than the others, but it is reasonable to choose the one that has the longer half-life and lower cost. Trandolapril, fosinopril, ramipril, and enalapril have average trough-peak ratios of 50% or greater [34], which may give a better BP control between dosing intervals. Because of the recent uniform pricing structure for some ACE inhibitors (regardless of the dose strengths), they may be less expensive when a higher dose is required or when the tablet is scored (Table 2). Generic captopril and enalapril also have become available with some cost advantage (see Table 2). Captopril has the disadvantages of multiple daily dosing and the rare adverse effects, such as neutropenia, nephrotic syndrome, and rashes, from its unique sulfhydryl group [37].

Table 1

The major differences in side effects between angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers

ACE-I ARBs Investigators

Bradykinin Increased No change Goodfriend et al, 1996 [32]

Cough 10% No Wright, 2000 [33]

Angioedema 0.1-0.5% <0.1-0.5% Warner et al, 2000 [35];

grossman, 2000 [36]

Hyperkalemia in patients Common May be less common Bakris et al, 2000 [37]

who have renal failure

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARBS, angiotensin II-receptor blockers.

Thiazide diuretics

Thiazide diuretics (TDs) increase the sodium chloride secretion in renal distal tubules. Their antihypertensive effects are not fully understood, but it is believed that TDs decrease BP by reducing plasma volume and peripheral resistance [38]. It is known that hypertensive, diabetic patients are salt sensitive and have increased peripheral vascular resistance [39]. Theoretically, TDs should work well in this group of patients because of their vasodilatory and diuretic effects. In the Systolic Hypertension in the Elderly Program (SHEP) trial, the CV event rate was reduced by 34% in hypertensive, diabetic patients who were assigned randomly to low-dosage chlorthalidone [40]. Diabetic patients benefited twice as much as nondiabetic patients from low-dosage chlorthalidone. The magnitudes of benefit may be underestimated because some patients who were assigned to the placebo group also received active therapy. Further analysis indicated that benefits in the treatment group were not attributable to the step 2 drugs (atenolol or to reserpine) in the overall group of hypertensives [41]. Subgroup analysis to evaluate the impact of atenolol in diabetics was not possible because of the small sample size. The major adverse effects from high-dosage TDs are hypokalemia, hyper-glycemia, and increased cholesterol. These effects are much less a concern when a low dosage is used [40]. An early observational study showed

Table 2

Price comparison of selected combination drugs for hypertension

Table 2

Price comparison of selected combination drugs for hypertension

Agent 1

Price of 30 tablets ($)

Agent 2

Price of 30 tablets ($)

Name of combination pill

Price of combination pill 30 tablets ($)

Chlorthalidone, 25 mg


Atenolol, 50 mga




HCTZ, 12.5 mg capsule


Valsartan, 80 mga


Diovan HCTa


HCTZ, 12.5 mg capsule


Irbesartan, 150 mg




HCTZ, 12.5 mg capsule


Losartan, 50 mg




HCTZ, 25 mg tablet


Benazepril, 20 mga


Lotensin HCTa


HCTZ, 12.5 mg capsule


Zestril, 10 mg




HCTZ, 12.5 mg capsule


Enalapril, 10 mg




Felodipine, 5 mg


Enalapril, 5 mg




Amlodipine, 5 mg


Benezepril, 10 mg






Trandolapril, 2 mga




Fosinopril, 20 mga


Ramipril, 5 mg


Captopril, 50 mg


Abbreviation: HCTZ, hydrochlorothiazide. a Very close or same price for different dosages.

b HCTZ, 25 mg, tablet can be split; 90 tablets of 25 mg or 50 mg cost $5.49.

c The price is for 60 tablets.

Data from

increased mortality in diabetic patients who received high-dosage TDs [42]. The most likely explanation was increased risk of fatal arrhythmia due to hypokalemia that was secondary to TDs [43].

b-Blockers b-Blockers (bBs) have been used in the treatment of hypertension for a long time. Although based on some studies, JNC V and VI recommended bBs as first-line therapy for hypertension; however, a recent meta-analysis raised some question by showing a marginal, but statistically insignificant, effect of bBs on CV morbidity and mortality in hypertensive patients [25]. bB-pla-cebo-controlled trials are not available in diabetic patients who have hypertension; however, because most diabetic patients die of CV complications, bBs should be considered strongly in hypertensive, diabetic patients. Atenolol was as effective as ACE inhibitors in reducing CV morbidity and mortality in diabetic, hypertensive patients in the UKPDS [3,5]. bBs also are preferable in diabetic patients who have CAD and always should be used in the postinfarction period because compared with nondiabetic patients, there is a significantly greater cardioprotective effect of bBs in diabetics [44]. Additionally, based on recent data, diabetic patients who have heart failure should be given bB therapy in addition to ACE inhibitor therapy.

A few unfavorable metabolic effects of bBs were reported. bBs might exacerbate glucose intolerance [5,45,46], increase triglycerides, and decrease high-density lipoproteins [47]. These effects on surrogate end points should not prevent us from using bBs in diabetic patients who have hypertension. Caution should be taken when using bBs in diabetic patients who are at risk for severe hypoglycemia, although there is no convincing evidence that b1-selective blockers increase the risk of masking hypoglycemia symptoms [48-50]. High dosages of selective b1-block-ers should be avoided in patients who have asthma or severe obstructive lung diseases. bBs should not be used in patients who have advanced heart block or sinus node disease without a pacemaker.

Calcium-channel blockers

CCBs have a neutral effect on carbohydrate metabolism [51] and low side-effect profiles. Subgroup analysis of elderly diabetic patients who had systolic hypertension from a placebo-

controlled trial (systolic hypertension in Europe trial investigators) clearly showed an impressive CV morbidity and total mortality reduction in the group that received nitrendipine alone [14]. Another large study, the Hypertension Optimal Treatment (HOT), demonstrated that the intensive control of BP, reduced the CV events more significantly than in the group whose BP was less tightly controlled [52]. The beneficial effects were of significantly greater magnitude in the diabetic cohort; however, many of the diabetic patients also received ACE inhibitors. Other recent studies, however, such as the Fosinopril/Amlodipine Event Trial (FACET) [53] and the Appropriate Blood Pressure Control in Diabetes (ABCD) [54] trials, showed that compared with ACE inhibitors, treatment with dihydropyridine CCBs in diabetic hypertensive patients might be harmful. This raised significant concern about the safety of dihydropyridine CCBs in these patients. Overall, CCBs are well-tolerated; the major side effects are headache, flushing, and ankle edema [55].

a-Adrenergic antagonists

AAAs decrease insulin resistance and cholesterol [56,57]. Theoretically, this class of drug may improve glycemic control in patients who have diabetes and improve long-term outcome. Findings from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), however, showed that patients who were on doxazosin had a higher risk of developing congestive heart failure, angina, and stroke than patients who were assigned to chlorthalidone [58]. The most plausible explanation is that these adverse effects occurred because AAAs increase plasma volume [59] and norepinephrine [60]. In addition, AAAs are less likely to regress left ventricular mass [61,62]. Based on the results of the ALLHAT, doxazosin should not be used as first-line drug for hypertension. Furthermore, it is recommended that bBs, in combination with a diuretic, should be added to a-adrenergic blockers in hypertensive, diabetic patients who are being treated for benign prostate hypertrophy. Alternatively, prostate-selective a-adrenergic blockers may be considered.

Angiotensin Il-receptor blockers

It is well-known that the production of an-giotensin II may not be blocked completely by ACE inhibitors because of the formation of angiotensin II by the non-ACE-dependent pathway [63]. Angiotensin II-receptor blockers (ARBs) act by blocking the effects of angiotensin II on angiotensin I receptors, and therefore, provide more complete blockade to the action of angiotensin II, regardless of its origin. Recently, the combination of ACE inhibitors and ARBs was more effective in decreasing BP and reducing proteinuria than either agent alone [64]. Another study showed that as monother-apy, ACE inhibitors and ARBs decreased the BP and urine protein to the same extent in diabetic patients who had hypertension [65]. In general, ARBs have a better side-effect profile than ACE inhibitors (see Table 1). In a recent trial, irbesartan was superior to amlodipine in improving creatinine clearance and reducing proteinuria in diabetic patients who had hypertension, despite similar antihypertensive effects [66].

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