Antihypertensive Therapy In Dm More Than Just Reducing Albuminuria

Since microalbuminuria is also is a strong predictor of all-cause and in particular cardiovascular mortality [75, 76, 78], the effects of these antihypertensive agents must include assessment of cardiovascular endpoints. In the ABCD study it was suggested that ACEI therapy was superior to dihydropyridine CCBs in conferring cardiovascular protection [89]. Similar findings were reported from the FACET study which suggested that fosinopril was associated with less cardiovascular events than amlodipine [90]. However, It was not clear from those small studies whether ACEI confer cardioprotective effects while the dihydropyridine CCB have a deleterious effect. It is likely that the ACEI may confer in certain contexts an additional beneficial effect rather than the CCBs having a deleterious effect on cardiovascular events in the DM2 population. For example, in the Syst-EUR study, a subgroup analysis of the diabetic cohort with systolic hypertension revealed a beneficial effect of nitrendipine on cardiovascular outcomes [91]. In the HOT study which involved randomisation of subjects to 3 different target blood pressures with a felodipine based regimen, analysis of the diabetic subgroup showed that the lowest blood pressure target group had the lowest incidence of cardiovascular morbidity and mortality [92].

This would suggest that blood pressure reduction per se is a major determinant of cardioprotection in this diabetic population. However, it must be appreciated that the group randomized to the lowest blood pressure group required the most concomitant antihypertensive agents, including ACE inhibitors and beta-blockers, which may have conferred additional cardioprotection. Within the diabetic subgroup in the CAPPP study, captopril was superior to conventional treatment (diuretic/beta blocker) despite similar blood pressure reduction [93, 94]. There was an approximately 40% decrease in the risk ratio for the primary end-point, combination of fatal and non-fatal myocardial infarction, stroke and other cardiovascular deaths, in patients receiving captopril compared to conventional therapy. In the UKPDS blood pressure reduction was clearly shown to reduce vascular events [95]. Further analysis revealed no difference between the group treated with captopril or atenolol [96]. However, in this study there was a very high level of non-compliance (20-40%) and over 60% of subjects were on 2 or more drugs.

The importance of ACE inhibitors in conferring macrovascular in addition to renal protection has been demonstrated in the HOPE study. In the diabetic subgroup, despite the fact that ramipril treatment was reported to reduce blood pressure by only 2/1 mmHg more than the control group, there was a 25%

decrease in cardiovascular death, myocardial infarction and stroke and a 24% decrease in total mortality [97]. This decrease in blood pressure with high dose ramipril as an add on treatment remains controversial with ambulatory blood pressure data obtained in a small subgroup from that study suggested greater reduction in blood pressure with active treatment [98]. In an early report on the hypertensive cohort in the ABCD study, Estacio et al demonstrated a reduction in overall mortality in those patients, which received intensive treatment [47]. Yet, they were unable to demonstrate a significant difference in cardiovascular events. However, in a recent report of the same study, including an analysis of both the hypertensive and normotensive cohorts, the investigators were able to show that intensive blood pressure control reduced the risk for a cardiovascular event in those patients, who had peripheral arterial disease [99]. The LIFE study was designed to determine the most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and left ventricular hypertrophy [100, 101]. This study included a diabetic cohort and within this group, the subjects were randomized to either losartan (586 patients) or atenolol (609 patients). The patients in both groups received non-trial antihypertensive drugs (excluding ACEI) in order to reduce blood pressure and were followed for a mean of 4.7 years. There was a difference of 2 mmHg mean systolic pressure between the groups. The risk reduction for the primary endpoint (cardiovascular morbidity or death) in the losartan group was 0.76 and for cardiovascular death was 0.63. However, that study did not include a significant number of patients with renal disease. A separate detailed analysis of the microalbuminuric subjects both diabetic and non-diabetic, in the LIFE study is eagerly awaited. In the RENAAL study, there was a significant decrease in first time admission to hospital for cardiac failure, amongst those subjects receiving losartan [4]. A similar, albeit non-statistical, benefit on hospitalization for heart failure was also reported in the IDNT study [6]. These studies showed that both ACEI and ARB have a substantial beneficial effect of the development of cardiovascular complications in DM2 patients.

Treatment with ACEI has also been shown in the CAPPP and HOPE study to reduce the number of patients developing de novo diabetes [94, 102]. Furthermore, in the LIFE study losartan treatment was associated with less development of diabetes than atenolol [100]. It still remains to be determined if these effects on the development of diabetes are linked to the deleterious effects of agents such as thiazide diuretics and beta blockers on glucose tolerance or the beneficial effects of agents, which interrupt the RAS, on insulin sensitivity. This issue remains controversial with Gress et al having reported in a large study of non-diabetic hypertensive subjects that treatment with thiazide diuretics, ACEI

or CCB was not associated with an increased risk for the development of diabetes, whereas beta-blockers increased the risk [103].

Nosadini and Tonolo have recently analyzed the effect of CCBs on cardiovascular complications [104]. They summarized the results of four trials, where patients were randomized to either CCB (dihydropyridine). ACEI or ARB [6, 89, 90, 105]. These authors reached the conclusion that CCB compared with conventional therapy resulted in an average of 25% fewer strokes and an average of 18% more non-fatal acute myocardial infarctions. Thus the ACEI and ARB drugs seem to be superior to CCB in reducing cardiovascular but not cerebrovascular risk. However, CCB do seem to reduce the risk for stroke. Indeed, such a pattern is further suggested by the ALLHAT study [106]. However, one must be cautious in over-interpreting the findings of the ALLHAT study to the diabetic population. Although 40% of participants had diabetes, there was a very high drop out rate, significant compliance issues and a much higher proportion of Afro-American subjects than seen in trials performed outside the United States.

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