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Prof. Guido Grassi
Observational studies have provided evidence that a consistent fraction (about 15-20%) of hypertensive patients display a glucose intolerance state which may be aggravated by antihypertensive drugs such as thiazide diuretics and/or beta blockers.
Data obtained from observational studies have shown that patients with untreated hypertension display an increased incidence of type II diabetes mellitus compared to the normotensive state (1). They have also shown that this phenomenon is made worse when thiazide diuretics or beta-blockers are administered chronically, i.e. that new onset diabetes is more frequent in hypertensive patients treated with these drugs than in untreated individuals, particularly when their administration is combined (2-4). This issue has become hotly debated, because of its implications in terms of the choice of drugs to employ for initial antihypertensive treatment in seeking to ensure maximal cardiovascular protection for the patient. The question is whether physicians should 1) disregard the above metabolic inconvenience, given the excellent blood pressure lowering effect of thiazide diuretics and beta-blockers as well as their ability to protect hypertensive patients from cardiovascular disease, 2) give great importance to this inconvenience and refrain from any large use of these drugs or 3) privilege a “flexible” attitude, i.e. impose no limits as to the use of diuretics and beta-blockers when patients are at high cardiovascular risk - and thus needing an effective and timely blood pressure reduction to less than 140 mmHg systolic and 90 mmHg diastolic-, but use them with caution when, as in younger or mild hypertensive patients, the more limited benefit to be expected from a blood pressure reduction may be neutralised or superseded by the increased cardiovascular risk associated with the occurrence of diabetes. An additional problem related to this last opinion is that of identifying those patients at high risk of becoming diabetics in whom diuretics and beta-blockers should not commonly represent first choice drugs.
One of the most striking findings from recent clinical trials has been the one concerning the class-differential effects on new-onset diabetes. Indeed, calcium channel blockers, ACE-inhibitors and angiotensin II receptor blockers all have a remarkable impact on the risk of new-onset diabetes, whereas any impact is less frequent when compared with older drug classes over relatively short trial durations of 3-6 years. There has been some debate over whether such data reflect a prodiabetic effect of older drugs, or an antidiabetic effect of the new ones. Evidence from trials, however, also shows a reduced incidence of new-onset diabetes in patients treated with ACE inhibitors or angiotensin II receptor blockers as compared with placebo (3,5,6), which suggests a “true” antidiabetic effect of new drugs. In this regard, some other trials are important. This is particularly the case when it comes to the Valsartan Long-term Use Evaluation (VALUE), which showed a significant benefit for the angiotensin II receptor blocker valsartan over amlodipine, a metabolically neutral calcium channel blocker (7).
A possibility which has been advanced is that the apparent diabetogenic effect of diuretics and beta-blockers simply reflects a “cosmetic” increase in blood glucose, with none of the adverse cardiovascular effects of true type 2 diabetes. Evidence that this is not the case has been provided by the CAPtopril Prevention Project (CAPPP) study performed on 6886 hypertensive patients enrolled into a treatment programme between 1973 and 1993 for an average of 6.3 years (8). For most of the treatment period, diuretics or beta-blockers were the first-line drugs. As expected, the incidence of cardiovascular disease during the study was significantly associated with raised blood glucose, whether measured at baseline or during treatment. Furthermore, patients who did not have raised blood glucose at baseline, but did have significantly raised levels (> 7.75 mmol/l) at some point in the study, had a 50% increased incidence of cardiovascular disease, a rate very similar to that of patients with raised blood glucose at baseline. Furthermore, in another study, a treatment-induced increase in blood glucose in patients aged 50 years was the major predicting factor for the occurrence of myocardial infarction at the age of 60 years (9). Based on these data, it seems that increases in blood glucose associated with antihypertensive treatment are just as serious as those that are a result of conventional risk factors.
Many more questions need to be answered to understand what a diabetic condition induced by antihypertensive drugs mean for cardiovascular preventive strategies. We need to know, for example, 1) whether the increased risk of developing diabetes with diuretics and beta-blockers becomes progressively greater with the increased duration of exposure to these drugs or 2) whether their effect just anticipates the inevitable, i.e. bringing on diabetic hypertensive individuals who will develop this condition a few years later anyway. We also need to know whether and how accurately patients that are more at risk of developing diabetes during antihypertensive treatment can be identified based on their demographic, clinical and/or genetic characteristics. Finally, although there is no question that the dysmetabolic effects of diuretics and beta-blockers are dose-dependent, it would be extremely important to know 1) whether diuretics have any diabetogenic effect when employed at low doses and 2) whether this effect can be entirely or partially counteracted by the antihypertensive agents with which low-dose diuretics are usually combined.
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. Mancia G. The association of hypertension and diabetes: prevalence, cardiovascular risk and protection by blood pression reduction. Acta Diabetol 2005; 42(Suppl.1):S17-S25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed 2. Law MR, Wald NJ, Morris JK, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12829555&query_hl=2 3. Eberly LE, Cohen JD, Prineas R, et al. Impact of incidence diabetes and incidence of non-fatal cardiovascular disease on 18-year mortality: the Multiple Risk Factor Intervention Trail Experience. Diabetes Care 2003;26:848-854. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12610048&query_hl=4 4. Opie LH, Schall R. Old antihypertensive and new diabetes. J Hypertens 2004;22:1453-1458. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15257162&query_hl=6 5. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertensive 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&dopt=Abstract&list_uids=11937179&query_hl=8 6. Hansson L, Lindholm L, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354:1751-1756. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10577635&query_hl=10 7. Lithell H, Hansson L, Skogg I, et al. The Study on Cognition and Prognosis in the elderly (SCOPE). Principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21:875-886. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12714861&query_hl=12 8. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet 1999;353:611-616; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10030325&query_hl=10 9. Hansson L, Hedner T, Lund-Johansen P, et al. Randomized trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359-365. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10972367&query_hl=16
Prof. G. Grassi Monza, Milan, Italy Chairman of the ESC Working Group on Hypertension and the Heart
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