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Prof. Guido Grassi
In diabetic hypertensive patients, the primary goal of the therapeutic intervention is to reduce blood pressure to the lowest tolerated values. However, evidence exists that in the therapeutic approach some antihypertensive drugs (ace-inhibitors and angiotensin II receptor blockers) may be preferred over other drugs particularly if renal dysfunction takes place.
It is well established that in the diabetic hypertensive patient a blood pressure lowering intervention has cardiovascular protective effects, independently of the drug used for achieving the therapeutic goal. This has been shown, for example, with the results of the SHEP Study (1), in which diabetic and non diabetic patients with isolated systolic hypertension displayed a clearcut reduction in cardiovascular mortality when blood pressure values were reduced with a thiazide diuretic, eventually combined with a beta blocking agent. This has also been shown in a number of others studies, which have demonstrated a clearcut reduction in cardiovascular complications in diabetic patients with systodiastolic or isolated systolic hypertension treated with calcium antagonists or ace-inhibitors (2-3). It thus appears that the first goal of the pharmacologic intervention is to lower blood pressure, taking into account that the benefit of the therapeutic intervention is directly related to the degree of the overall risk profile of the patient before the start of the treatment. This means that in the diabetic patient, -usually a very high risk profile- blood pressure reduction exerts extremely favourable results in reduction of both morbidity and mortality. This is further confirmed by the Syst-EUR trial, in which the antihypertensive intervention in aged diabetic individuals with isolated systolic hypertension caused a reduction in the cardiovascular risk almost double the one found in non diabetic hypertensives (2).
The 2003 Guidelines for management of hypertension issued by the European Society of Hypertension and the European Society of Cardiology (4) have clearly established that “the primary goal of antihypertensive treatment in diabetics is to lower blood pressure below 130/80 mmHg whenever possible, the optimal blood pressure being the lowest one that remains tolerated”. The above mentioned therapeutic goal is based on the results of different studies, such as the UKPDS, the HOT and the ABCD Trials (5-7), which have provided conclusive evidence on the favourable effects of “aggressive” treatment of hypertension. In the UKPDS study, the reduction in cerebrovascular events amounted to 44%, while for the HOT and ABCD studies, cardiovascular mortality and total mortality were 43 and 49% respectively. It should also be emphasised that in high risk patients as hypertensive diabetics are, a difference of even a few millimeters of mercury may greatly effect results in term of reduction in cardiovascular events. This has been shown in the HOPE study (8) and in the already quoted HOT study (6), in which the reduction in cardiovascular morbidity in the group achieving diastolic blood pressure levels of 81 mmHg was about double the one in patients with 85 mmHg. As also stressed by the ESH/ESC Guidelines, to reach the above mentioned goal, a combination of two or more drugs is most often required (4).
All antihypertensive drugs with documented efficacy may be used in the diabetic hypertensive patient, also taking into account that the first goal of treatment is to lower blood pressure and the global cardiovascular risk profile. In the case of type 1 diabetes no trial has been performed so far with the aim of 1) assessing the effect of blood pressure lowering on cardiovascular morbidity and mortality and 2) comparing the effects of different drugs on these endpoints. There is evidence, however, that in these patients diuretic or beta blocker treatment may delay the prognosis of nephropathy while in patients already displaying renal damage -documented by the presence of albuminuria- blockade of the renin-angiotensin system via ACE inhibitors appears to be the therapeutic choice capable of guaranteeing the best protection against the onset of renal dysfunction.
In contrast, a number of studies that have been reviewed recently (8) have evaluated the effects of antihypertensive drugs on cardiovascular events in type 2 diabetes. Overall it is difficult to affirm that one class of drugs is superior to the others, taking into account that only two studies have shown a superiority of ACE inhibitors (vs diuretics / beta blockers and calcium antagonists) (3,7). No difference was found between diuretics, ace inhibitors and calcium antagonists in the ALLHAT Study which enrolled a large number of hypertensive diabetics (9). The equality of different drugs, however, does not appear to include angiotensin II receptor blockers, which in the LIFE study have demonstrated a greater efficacy on cardiovascular events, cardiovascular death and total mortality than beta blockers (10). This appears to be the case also for the choice of the antihypertensive agent in patients with diabetic nephropathy in which the recommendation of obtaining a very strict blood pressure control deserves to be coupled with the need to employ drugs which effectively block the adverse effects of angiotensin II, such as ACE inhibitors and angiotensin II receptor blockers. A particular nephroprotection appears to be guaranteed by these latter drugs, as documented by the results of the RENAAL and IDNT studies (11,12).
In diabetic hypertensive patients, it can thus be recommended (4) to use all effective and well tolerated antihypertensive agents to achieve an optimal blood pressure control, ie values below 130/80 mmHg. Among the different antihypertensive drugs a particular place should be made for ace inhibitors and angiotensin II receptor blockers, taking into account the ability of these drugs to exert nephroprotection. Finally the finding of microalbuminuria in type 1 or type 2 diabetes requires the use of agents which effectively block the renin-angiotensin system.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. SHEP Cooperative Research Group. Prevention of stroke by hypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255-3324
2. Tuomilehto J, Rastenyte D, Birkenhager WH et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension: Systolic hypertension in Europe Trial Investigators. N Engl J Med 1999;340:677-684 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10053176&dopt=Abstract
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6. Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-1762 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9635947&dopt=Abstract
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8. Zanchetti A, Ruilope LM. Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials? J Hypertens 2002;20:2099-2110 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12409940&dopt=Abstract
9. The ALLHAT Officiers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12479763&dopt=Abstract
10. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For End-point reduction in hypertention study (LIFE): a randomized trial against atenolol. Lancet 2002;359:1004-1010 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11937179&dopt=Abstract
11. Brenner BM, Cooper ME, De Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:851-860 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11601117&dopt=Abstract
12. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effects of angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:870-878 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11565517&dopt=Abstract
Prof. G. Grassi Monza-Milan, Italy Vice-Chairman of the ESC Working Group on Hypertension and the Heart
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