Cardiovascular and Cerebrovascular Trials Along with Renal Endpoints

Cardiovascular and Cerebrovascular Trials Along with Renal Endpoints

Cardio- and also cerebrovascular diseases are important causes of death in both type 1 and type 2 diabetes, especially when the kidney is affected.

Although the concept of controlled clinical or therapeutical trial has evolved

Table 5. Positive effect on cardiovascular endpoints in type 2 diabetes by antihypertensive treatment

Favors

1. Shep [Curb et al.]

Diurectics vs. placebo

2. ABCD [Estacio et al.]

ACE-I vs. CCB

3. Facet [Tatti et al.]

ACE-I vs. CCB

4. HOT [Hansen et al.]

Strict control (CCB-based)

5. UKPDS [Turner et al.] Strict control (ACE-I +b-blocker-based) 7. CAPP [Hansson et al.]

ACE-I vs. conventional

8. Syst-Eur [Toumilehto et al.]

CCB vs. placebo

9. Hope-study [Yusef et al.]

ACE-I vs. placebo

CCB>Calcium channel blockers.

over the past 50 years, only a few large trials have been conducted in diabetes, the first being the UGDP (University Group Diabetes Program) which now after the UKPDS, is mainly of historical interest. No real large-scale controlled trials were done when introducing sulfonylureas, biguanides or insulin, but this has changed now with the UKPDS. There has therefore been an increasing interest in cerebro- and cardiovascular endpoints, especially in type 2 diabetes with respect to effective modulation, mainly with antihypertensive treatment strategies, which show a beneficial effect (table 5). Most studies employ ACE inhibitors but it is noteworthy that any reduction of BP seems to be important. Certain trials show ACE inhibitors to be superior to calcium blockers and also conventional treatment. Importantly, the UKPDS showed a similar out- come using ACE inhibitors and b-blockers. Fewer side effects occurred with the use of ACE inhibitors. This study also clearly showed that careful BP monitoring and effective treatment reduced cardio- and microvascular end- points very considerably (around 30%). Therefore, antihypertensive treatment should be given a great priority in the management of patients with type 2 diabetes. The UKPDS showed some effect of optimal glycemic control, but due to the nature of the trial this was not so evident. However, combined

euglycemia (HbA 1c B6–7%) and normotension is highly protective when BP is around 130–135/80–85 mm Hg.

Guidelines with Origin in Pathophysiological and Clinical Trials

The World Health Organization-International Society of Hypertension (WHO-ISH) Liaison Committee on Hypertension was established in the mid-

Table 6. Suggested target BPs during antihypertensive treatment (systolic and diastolic should be attained, e.g. =140/85 mm Hg means =140 systolic and =85 diastolic)

Clinic BP ABPM or home BP

no diabetes 1 diabetes Titrate to diastolic BP p85

no diabetes 1 diabetes

p 80 p 80 p 75 Optimal BP

= 125/75 Suboptimal BP

p 130/80 ABM>Ambulatory blood pressure monitoring.

1 In those with high cardiovascular risk and initial BP 140–159/90–99 mm Hg there could be a case for adopting the targets for diabetic patients (British

Hypertension Society 1999).

1970s and has subsequently produced several guidelines, the first in 1975. New guidelines have recently appeared also related to hypertension in diabetes. Several of these new guidelines have a similar approach. There is a clear emphasis on early and effective antihypertensive treatment in patients with diabetes suggesting a lower threshold for the start of the treatment and also

a lower goal during treatment. ACE inhibitors are often preferred as initial agents but combination therapy is often warranted. In view of the recent observation that different types of drugs (ACE-I, b-blockers, calcium channel blockers and diuretics) reduce cardiovascular risks in type 2 diabetes, there are different treatment options. In diabetic renal disease, ACE-I is however preferred. We should aim to achieve a BP around 135/85 mm Hg during treatment, or lower.

The British Hypertension Society proposes: (1) ‘ The threshold for antihy- pertensive treatment in type 1 diabetes is q140/90 mm Hg. The target BP is = 130/80 mm Hg, or lower (=125/75 mm Hg) when there is proteinuria q 1 g/24 h’. And (2): ‘Trials support treatment of all patients with type 2 diabetes and BP q140/90 mm Hg, aiming for a target BP =130/80 mm Hg. BPs p140/85 mm Hg on treatment should be considered suboptimal.’ (3) ‘ Thus there is evidence from outcome trials in hypertensive patients with diabetes for the efficacy and safety of ACE inhibitors, b-blockers, dihydropyrid- ines, and low-dose thiazides. The choice among these drug classes should be made using the criteria set out for nondiabetic patients. BP control will usually require more than one antihypertensive drug, and about 30% of hypertensive patients with diabetes need three or more agents in combination.’ A similar approach is seen in table 6.

The problem is that it may be difficult to achieve such BP with patients with proteinuria and overt renal disease and also in others with cardiovascular

problems. Therefore, it is strongly advocated to start treatment early, e.g. with development of microalbuminuria, even in patients with normal BP. It has also been proposed to start treatment even before microalbuminuria. Since complications are so closely associated with BP increase (also in the normal range) this could easily be recommended in future guidelines as we now have effective treatment modalites with rather limited side effects.