Management of hypertension

Weight reduction has been shown to be an effective non-pharmacological approach to improve blood pressure in several studies (Schotte and Stunkard, 1990; Krzesin-ski et al., 1993). Loss of 1 kg body weight is associated with a mean decrease in blood pressure of 1 mmHg (Staessen et al., 1989). The reduction in blood pressure is related to the amount of weight loss rather than to the various treatment modalities employed such as different caloric restrictions or behaviour therapy. Weight reduction can also reduce the number of antihypertensive medications prescribed (Fagerberg et al., 1984).

The role of sodium restriction is controversial. The INTERSALT Study showed that dietary sodium restriction can independently lower blood pressure and is additive with weight loss (Fagerberg et al., 1984). Studies have shown that moderate sodium restriction to 100 mmol (2300 mg) per day can reduce systolic pressure by 5 mmHg and diastolic pressure by 2-3 mmHg (Cutler et al., 1997). In addition, the response to antihypertensive therapy appears to be more effective in salt-restricted subjects. Physical activity, involving 30-45 min of brisk walking has been shown to lower blood pressure, as well as smoking cessation, and reduction of alcohol intake (Joint National Committee, 1997; Haire-Joshu et al., 1999; American Diabetes Association, 2002).

A number of large studies in diabetic patients with hypertension have shown important benefits in CHD outcomes from lowering blood pressure (UKPDS, 1998; Heart Outcomes Prevention Evaluation Study, 2000). The UKPDS showed that tight blood pressure group was associated with significant reduction in macrovascular complications compared to the less intensively treated group (10/5 mmHg difference between the groups) (UKPDS, 1998).

Proteinuria is considered as a harbinger for CHD as well as renal disease and it is postulated that angiotensin-converting enzyme (ACE) inhibitors may offer some unique benefit in preventing CHD as well as nephropathy in type 2 diabetes. Indeed, in the Heart Outcomes Prevention Evaluation substudy, (MICRO-HOPE) and in the Captopril Prevention Project (CAPPP) Trial, the

Table 9.1 Major hypertension trials in subjects with diabetes

n

n

Follow up

Main

Endpoint reduction

Study

randomized

diabetes

(years)

comparison

(diabetes)

UKPD

1148

1148

9

Captopril versus

Diabetes related

atenolol

death 32%

Stroke 44%

SHEP

4736

583

5

Chlorthalidone

All cardiovascular

versus placebo

events (46-66%)

CAPPP

10985

572

6

Captopril versus ß

Captopril group

blocker or

fatal/non-fatal

thiazide

34%

SYS-Euro

4695

492

2

Nitrendipine

All major

versus Placebo

cardiovascular

events (41-70%)

HOT

18790

1501

4

Felodipine

All cause mortality

39%

MICRO-HOPE

3577

4.5

Ramipril versus

Total mortality 29%

Placebo

CV deaths 37%

MI 22%

ALLHAT

24335

8633

4.9

Amlodipine,

Total mortality

doxazosin,

-39%

lisinopril,

chlorthalidone

LIFE

9193

1195

4.8

Losartan versus

Losartan group all

atenolol

cause mortality

39%

ABCD

470

470

5

Nisoldipine versus

Discontinuation of

enalapril

study

CV, cardiovascular; MI, myocardial infarction; UKPD, UK Prospective Diabetes; HOPE, heart outcomes Prevention Evaluation; HOT, hypertension optimal treatment; SHEP, systolic Hypertension Elderly Program; CAPPP, Captopril Prevention Project Trial; SYST-EURO, Systolic Hypertension Europe; MICRO, Microalbuminuria Cardiovascular and Renal Outcomes; ALLHAT, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; LIFE, Losartan Intervention For Endpoint Reduction Study; ABCD, Appropriate Blood Pressure Control in Diabetes.

CV, cardiovascular; MI, myocardial infarction; UKPD, UK Prospective Diabetes; HOPE, heart outcomes Prevention Evaluation; HOT, hypertension optimal treatment; SHEP, systolic Hypertension Elderly Program; CAPPP, Captopril Prevention Project Trial; SYST-EURO, Systolic Hypertension Europe; MICRO, Microalbuminuria Cardiovascular and Renal Outcomes; ALLHAT, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; LIFE, Losartan Intervention For Endpoint Reduction Study; ABCD, Appropriate Blood Pressure Control in Diabetes.

diabetic subgroup on ACE inhibitors had better cardiovascular outcome events (Table 9.1) (HOPES, 2000).

Further studies involving ACE inhibitors, the FACET (Fosinopril vs Amlodip-ine Cardiovascular Randomized Events Trial) and the ABCD trial (Appropriate Blood Pressure Control in Diabetes) appeared to suggest that calcium channel blockers might be inferior to ACE-I in the context of cardiovascular disease and/or the beneficial outcome observed is a reflection of the cardioprotective effect of an ACE inhibitor. These studies should be interpreted with caution as the trials were not designed and powered to assess a difference between two treatment groups with regard to cardiovascular events (Tatti et al., 1998; Estacio et al., 2000).

The controversy surrounding the calcium antagonist therapy with regard to adverse cardiovascular events was not demonstrated in the Systolic Hypertension

Europe (SYS-Eur) Trial and the Hypertension Optimal Treatment Study (HOT) (see Table 9.1; Hansson et al., 1998; Tuomilehto et al., 1999).

The HOT Study also looked at the optimal diastolic target blood pressure. Felodipine was used as an initial treatment with other agents introduced in a five step regime to achieve the diastolic target value <90mmHg, <85mmHg or <80mmHg. Among the diabetic group, aggressive diastolic blood pressure lowering to less than 80 mmHg was associated with the 51 per cent reduction in the risk of major cardiovascular events and 43 per cent reduction in the risk of cardiovascular mortality (Hansson et al., 1999).

Similarly, much has been debated about the adverse effects of diuretic therapy especially in diabetic subjects. The beneficial effect of chlorthalidone as an antihypertensive agent was seen in the Systolic Hypertension in the Elderly Program (SHEP), which demonstrated reduction in major cardiovascular events in older type 2 diabetics and non-diabetics who had isolated systolic hypertension (ISH). (Table 9.1; Curb et al, 1996).

Recently published data from the largest hypertensive trial, ALLHAT (33 357 subjects), compared the effect on cardiovascular endpoints of three newer agents (amlodipine, lisinopril or doxazosin) with a diuretic (chlorthalidone). After a mean follow up of 4.9 years, there was no difference in the relative risk of the primary outcome (combined fatal CHD or non-fatal myocardial infarction) or all cause mortality between amlodipine, lisinopril and chlorthalidone (Table 9.1; ALLHAT Collaborative Group, 2002).

These studies have not shown particular benefits of the newer drug classes compared with long established agents. The recent understanding of the role of A II in the pathogenesis of atherosclerosis and it's effect on myocardial tissues might suggest that A II type 1 receptor blockers (ARB) may prove to have genuine drug class differences in relation to cardiovascular outcomes.

Indeed, the LIFE (Losartan Intervention For Endpoint Reduction) Study looked at the effect of losartan or atenolol on 9193 hypertensive patients with left ventricular hypertrophy. Losartan not only reduced the cardiovascular outcomes, but there was approximately a two-fold greater ECG-left ventricular hypertrophy regression compared with the atenolol group. More impressive results were seen in sub-set of 1195 patients with diabetes, with a 39 per cent risk reduction in all cause mortality compared with the atenolol group. These benefits were above and beyond those attributable to blood pressure reduction alone (Table 9.1; Dahlof et al., 2002).

Recently, three large placebo-controlled trials involving ARBs have demonstrated reduction of progression of albuminuria and the development and progression of nephropathy in hypertensive patients with type 2 diabetes. These differences were not explained by the blood pressure reduction achieved. It is postulated that ARBs have renal protective effects over and above blood pressure lowering in patients with type 2 diabetes (Brenner et al., 2001; Lewis et al., 2001; Parving et al. 2001).

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