Effect of Antihypertensive Agents on the Development of Type 2 Diabetes Mellitus
2006; Elsevier BV; Volume: 81; Issue: 6 Linguagem: Inglês
10.4065/81.6.796
ISSN1942-5546
AutoresCraig S. Stump, Marc T. Hamilton, James R. Sowers,
Tópico(s)Sodium Intake and Health
ResumoPeople with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and β-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population. People with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and β-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population. Evidence of a causal relationship between insulin resistance and hypertension is increasing.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar Untreated patients with essential hypertension generally have higher fasting and postprandial insulin levels than normotensive patients regardless of body mass. A direct correlation exists between blood pressure and fasting insulin levels with essential hypertension,1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar, 2Denker PS Pollock VE Fasting serum insulin levels in essential hypertension: a meta-analysis.Arch Intern Med. 1992; 152: 1649-1651Crossref PubMed Google Scholar, 3Grunfeld B Balzareti M Romo M Gimenez M Gutman R Hyperinsulinemia in normotensive offspring of hypertensive parents.Hypertension. 1994; 23: I12-I15Crossref PubMed Google Scholar, 4Reaven GM Lithell H Landsberg L Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.N Engl J Med. 1996; 334: 374-381Crossref PubMed Scopus (1095) Google Scholar, 5Steinberg HO Chaker H Leaming R Johnson A Brechtel G Baron AD Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance.J Clin Invest. 1996; 97: 2601-2610Crossref PubMed Google Scholar, 6McFarlane SI Banerji M Sowers JR Insulin resistance and cardiovascular disease.J Clin Endocrinol Metab. 2001; 86: 713-718Crossref PubMed Scopus (328) Google Scholar which does not occur with secondary hypertension.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar Insulin resistance and hyperinsulinemia are found in animal models of genetic hypertension.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar Thus, insulin resistance and hyperinsulinemia are not consequences of hypertension. Rather, they may reflect a genetic predisposition that contributes to and links these disorders.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar, 6McFarlane SI Banerji M Sowers JR Insulin resistance and cardiovascular disease.J Clin Endocrinol Metab. 2001; 86: 713-718Crossref PubMed Scopus (328) Google Scholar This concept is supported by the finding of altered glucose metabolism in normotensive offspring of parents with hypertension3Grunfeld B Balzareti M Romo M Gimenez M Gutman R Hyperinsulinemia in normotensive offspring of hypertensive parents.Hypertension. 1994; 23: I12-I15Crossref PubMed Google Scholar and further by the discovery of specific genetic defects in persons with combinations of insulin resistance, dyslipidemia, and hypertension, which has been reviewed previously.7Roche HM Phillips C Gibney MJ The metabolic syndrome: the crossroads of diet and genetics.Proc Nutr Soc. 2005; 64: 371-377Crossref PubMed Scopus (68) Google Scholar, 8Groop L Genetics of the metabolic syndrome.Br J Nutr. 2000; 83: S39-S48PubMed Google Scholar Likewise, in utero fetal programming has been implicated in predisposing individuals to insulin-resistant metabolic disease.9McMillen IC Robinson JS Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.Physiol Rev. 2005; 85: 571-633Crossref PubMed Scopus (721) Google Scholar, 10Stocker CJ Arch JR Cawthorne MA Fetal origins of insulin resistance and obesity.Proc Nutr Soc. 2005; 64: 143-151Crossref PubMed Scopus (66) Google Scholar However, the relative contributions of genetic, fetal, and postnatal environmental factors to overall risk remain uncertain. Evidence exists that insulin resistance and hyperinsulinemia predispose patients to the development of hypertension through cellular abnormalities in insulin signaling and associated hemodynamic and metabolic derangements.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar, 4Reaven GM Lithell H Landsberg L Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.N Engl J Med. 1996; 334: 374-381Crossref PubMed Scopus (1095) Google Scholar, 6McFarlane SI Banerji M Sowers JR Insulin resistance and cardiovascular disease.J Clin Endocrinol Metab. 2001; 86: 713-718Crossref PubMed Scopus (328) Google Scholar These predisposing abnormalities include cellular cation imbalance, enhanced sympathetic nervous system activity,4Reaven GM Lithell H Landsberg L Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.N Engl J Med. 1996; 334: 374-381Crossref PubMed Scopus (1095) Google Scholar enhanced tissue renin-angiotensin system activity,11Blendea MC Jacobs D Stump CS et al.Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.Am J Physiol Endocrinol Metab. 2005; 288: E353-E359Crossref PubMed Scopus (87) Google Scholar, 12Lavoie JL Bianco RA Sakai K Keen HL Ryan MJ Sigmund CD Transgenic mice for studies of the renin-angiotensin system in hypertension.Acta Physiol Scand. 2004; 181: 571-577Crossref PubMed Scopus (16) Google Scholar and increased inflammation and oxidative stress.1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar It also is becoming increasingly clear that antihypertensive medications have disparate effects on insulin sensitivity in patients with essential hypertension.13Perez-Stable E Caralis PV Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.Am Heart J. 1983; 106: 245-251Abstract Full Text PDF PubMed Google Scholar, 14Lithell HO Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.Diabetes Care. 1991; 14: 203-209Crossref PubMed Google Scholar, 15Harper R Ennis CN Sheridan B Atkinson AB Johnston GD Bell PM Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.BMJ. 1994; 309: 226-230Crossref PubMed Google Scholar, 16Fletcher A Amery A Birkenhager W et al.Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.J Hypertens. 1991; 9: 225-230Crossref PubMed Google Scholar, 17Savage PJ Pressel SL Curb JD SHEP Cooperative Research Group et al.Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program.Arch Intern Med. 1998; 158: 741-751Crossref PubMed Scopus (172) Google Scholar, 18Verdecchia P Reboldi G Angeli F, L et al.Adverse prognostic significance of new diabetes in treated hypertensive subjects.Hypertension. 2004; 43: 963-969Crossref PubMed Scopus (334) Google Scholar, 19Pollare T Lithell H Selinus I Berne C Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.BMJ. 1989; 298: 1152-1157Crossref PubMed Google Scholar, 20Lithell H Pollare T Vessby B Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.Blood Press. 1992; 1: 92-101Crossref PubMed Google Scholar, 21Samuelsson O Hedner T Berglund G Persson B Andersson OK Wilhelmsen L Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.J Hum Hypertens. 1994; 8: 257-263PubMed Google Scholar, 22Gress TW Nieto FJ Shahar E Wofford MR Brancati FL Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.N Engl J Med. 2000; 342: 905-912Crossref PubMed Scopus (631) Google Scholar, 23Sowers JR Bakris GL Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].N Engl J Med. 2000; 342: 969-970Crossref PubMed Scopus (74) Google Scholar, 24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar Both diuretics and β-blockers are reported to accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension.13Perez-Stable E Caralis PV Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.Am Heart J. 1983; 106: 245-251Abstract Full Text PDF PubMed Google Scholar, 14Lithell HO Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.Diabetes Care. 1991; 14: 203-209Crossref PubMed Google Scholar, 15Harper R Ennis CN Sheridan B Atkinson AB Johnston GD Bell PM Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.BMJ. 1994; 309: 226-230Crossref PubMed Google Scholar, 16Fletcher A Amery A Birkenhager W et al.Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.J Hypertens. 1991; 9: 225-230Crossref PubMed Google Scholar, 17Savage PJ Pressel SL Curb JD SHEP Cooperative Research Group et al.Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program.Arch Intern Med. 1998; 158: 741-751Crossref PubMed Scopus (172) Google Scholar, 18Verdecchia P Reboldi G Angeli F, L et al.Adverse prognostic significance of new diabetes in treated hypertensive subjects.Hypertension. 2004; 43: 963-969Crossref PubMed Scopus (334) Google Scholar, 19Pollare T Lithell H Selinus I Berne C Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.BMJ. 1989; 298: 1152-1157Crossref PubMed Google Scholar, 20Lithell H Pollare T Vessby B Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.Blood Press. 1992; 1: 92-101Crossref PubMed Google Scholar, 21Samuelsson O Hedner T Berglund G Persson B Andersson OK Wilhelmsen L Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.J Hum Hypertens. 1994; 8: 257-263PubMed Google Scholar, 22Gress TW Nieto FJ Shahar E Wofford MR Brancati FL Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.N Engl J Med. 2000; 342: 905-912Crossref PubMed Scopus (631) Google Scholar, 23Sowers JR Bakris GL Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].N Engl J Med. 2000; 342: 969-970Crossref PubMed Scopus (74) Google Scholar, 24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar The greater incidence of diabetes in reports comparing diuretics and β-blockers with angiotensin-converting enzyme (ACE) inhibitors may reflect in part the beneficial effects of ACE inhibitors on glucose metabolism.24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar, 25Hansson 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) randomised trial.Lancet. 1999; 353: 611-616Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar, 26Brown MJ Palmer CR Castaigne A et al.Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [published correction appears in Lancet. 2000;356:514].Lancet. 2000; 356: 366-372Abstract Full Text Full Text PDF PubMed Google Scholar, 27Black HR Elliott WJ Grandits G et al.Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.JAMA. 2003; 289: 2073-2082Crossref PubMed Scopus (415) Google Scholar, 28Pepine CJ Handberg EM Cooper-DeHoff RM INVEST Investigators et al.A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.JAMA. 2003; 290: 2805-2816Crossref PubMed Scopus (726) Google Scholar Compared with calcium channel blockers (CCBs), which are generally considered metabolically neutral,29McFarlane SI Farag A Sowers J Calcium antagonists in patients with type 2 diabetes and hypertension.Cardiovasc Drug Rev. Summer 2003; 21: 105-118Crossref PubMed Google Scholar diuretics and β-blockers are associated with new-onset diabetes mellitus.24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar, 26Brown MJ Palmer CR Castaigne A et al.Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [published correction appears in Lancet. 2000;356:514].Lancet. 2000; 356: 366-372Abstract Full Text Full Text PDF PubMed Google Scholar, 27Black HR Elliott WJ Grandits G et al.Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.JAMA. 2003; 289: 2073-2082Crossref PubMed Scopus (415) Google Scholar In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial (ALLHAT),24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar the diuretic chlorthalidone was 43% more likely to be associated with diabetes than the ACE inhibitor lisinopril and 18% more likely than the CCB amlodipine. However, these calculations only account for those individuals whose glucose values increased to greater than 126 mg/dL at 4 years not those who started taking the medication for diabetes during follow-up. Nevertheless, diuretics have consistently demonstrated their ability toreduce the cardiovascular mortality in patients with diabetes. ALLHAT concluded that thiazide diuretics comparably reduced all-cause mortality, such as stroke, coronary artery disease, and heart failure.30ALLHAT Officers and Coordinators, 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) [published corrections appear in JAMA. 2003;289:178 and 2004;291:2196].JAMA. 2002; 288: 2981-2997Crossref PubMed Scopus (3220) Google Scholar Therefore, diuretics continue to play an important role in the management of hypertension in patients with diabetes, especially as an adjunct to ACE inhibitors and angiotensin receptor blockers (ARBs). Evidence is accumulating that overcoming insulin resistance with antihypertensive agents that interrupt the reninangiotensin system may prevent or delay the emergence of type 2 diabetes mellitus in patients with essential hypertension1Sowers JR Insulin resistance and hypertension.Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602Crossref PubMed Scopus (237) Google Scholar, 31McFarlane SI Kumar A Sowers JR Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.Am J Cardiol. 2003; 91: 30H-37HAbstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar (Table 1). The Captopril Prevention Project was the first controlled clinical trial to show that an ACE inhibitor reduces the development of diabetes in patients with hypertension.25Hansson 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) randomised trial.Lancet. 1999; 353: 611-616Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar This trial was designed to compare the effect of ACE inhibition with conventional antihypertensive therapy (β-blocker, diuretic, or both) on cardiovascular morbidity and mortality. The number of patients with newly diagnosed diabetes was 14% lower in the captopril group than in the group receiving conventional therapy. These data were confirmed in the Heart Outcomes Prevention Evaluation trial in which a fixed dose of ramipril or placebo was added to whatever other therapy was prescribed for patients at high risk of cardiovascular events (including β-blockers, CCBs, and diuretics).32Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376 and 2000;342:748].N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (5912) Google Scholar During the 4.5-year trial, 35% fewer patients in the ramipril group than in the placebo (control) group developed diabetes (3.6% of the 4645 patients in the ramipril group vs 5.4% of the 4652 patients in the placebo group). The same percentage of patients (39%) in the ramipril and placebo groups were receiving a β-blocker at baseline. In addition, a retrospective analysis of data from one site that followed up 292 patients, the Studies of Left Ventricular Dysfunction, showed a relative risk reduction of 74% for developing diabetes during the 2.9-year study period in patients receiving enalapril compared with those receiving placebo (incidence of diabetes, 5.9% with enalapril vs 22.4% with placebo).33Vermes E Ducharme A Bourassa MG Lessard M White M Tardif JC Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD).Circulation. 2003; 107: 1291-1296Crossref PubMed Scopus (150) Google Scholar It has been suggested that, by blocking both kininase II and ACE, ACE inhibitors may increase not only nitric oxide production but also bradykinin, thus improving blood flow to skeletal muscle, properties that should improve insulin-mediated glucose uptake.31McFarlane SI Kumar A Sowers JR Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.Am J Cardiol. 2003; 91: 30H-37HAbstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 39Henriksen EJ Jacob S Kinnick TR Youngblood EB Schmit MB Dietze GJ ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide.Am J Physiol. 1999; 277: R332-R336PubMed Google ScholarTABLE 1Summary of Published Studies of Antihypertensive Agents That May Prevent or Delay Emergence of Type 2 Diabetes Mellitus in Patients With Essential Hypertension*ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial; ALPINE = Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; CAPPP = Captopril Prevention Project; CHARM = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; HOPE = Heart Outcomes Prevention Evaluation; INVEST = International Verapamil-Trandolapril Study; LIFE = Losartan Intervention for Endpoint Reduction in Hypertension; PEACE = Prevention of Events with Angiotensin Converting Enzyme Inhibition; SOLVD = Studies of Left Ventricular Dysfunction; SR = sustained release; VALUE = Valsartan Antihypertensive Long-term Use Evaluation.TreatmentRiskReferenceNo. of patientsPatient groupActiveControlTreated groupControl groupAbsolute risk reduction (%)Relative risk reduction (%)CAPPP25Hansson 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) randomised trial.Lancet. 1999; 353: 611-616Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar10,985Men and women 25–66 y with diastolic hypertensionCaptoprilβ-Blocker, diuretic6.16.90.811HOPE32Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376 and 2000;342:748].N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (5912) Google Scholar9297Men and women >55 y with cardiovascular diseaseRamiprilPlacebo3.65.41.833ALLHAT24Barzilay JI Pressel S Davis BR et al.Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.Am J Hypertens. 2004; 17: 1ACrossref PubMed Google Scholar15,573Men and women ≥55 y with hypertension and at risk of cardiovascular diseaseLisinoprilChlorthalidone or amlodipine8.111.6 and 9.83.5 and 1.730 and 17SOLVD33Vermes E Ducharme A Bourassa MG Lessard M White M Tardif JC Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD).Circulation. 2003; 107: 1291-1296Crossref PubMed Scopus (150) Google Scholar291Men and women 18–80 y with left ventricular dysfunctionEnalaprilPlacebo5.922.416.574LIFE34Lindholm LH Ibsen H Borch-Johnsen K LIFE Study Group et al.Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.J Hypertens. 2002; 20: 1879-1886Crossref PubMed Scopus (309) Google Scholar7998Men and women 55–80 y with hypertension and left ventricular hypertrophyLosartanAtenolol6.08.02.025CHARM35Pfeffer MA Swedberg K Granger CB CHARM Investigators and Committees et al.Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.Lancet. 2003; 362: 759-766Abstract Full Text Full Text PDF PubMed Scopus (1144) Google Scholar3023Men and women >18 y with heart failure grade II-IVCandesartanPlacebo3.15.12.039ALPINE36Lindholm LH Persson M Alaupovic P Carlberg B Svensson A Samuelsson O Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).J Hypertens. 2003; 21: 1563-1574Crossref PubMed Scopus (283) Google Scholar392Mostly women 18–75 y with newly detected hypertensionCandesartanHydrochloro-thiazide0.54.13.688VALUE37Julius S Kjeldsen SE Weber M VALUE Trial Group et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regi-mens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Abstract Full Text Full Text PDF PubMed Scopus (1643) Google Scholar10,419Men and women ≥50 y with hypertension and at high risk of cardiovascular diseaseValsartanAmlodipine13.116.43.323INVEST28Pepine CJ Handberg EM Cooper-DeHoff RM INVEST Investigators et al.A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.JAMA. 2003; 290: 2805-2816Crossref PubMed Scopus (726) Google Scholar16,176Men and women ≥50 y with hypertension and cardiovascular diseaseVerapamil SR, adding in order trandolapril, hydrochloro-thiazideAtenolol, adding in order hydro-chlorothiazide, trandolapril8.27.01.215PEACE38Braunwald E Domanski MJ Fowler SE PEACE Trial Investigators et al.Angiotensin-converting-enzyme inhibition in stable coronary artery disease.N Engl J Med. 2004; 351: 2058-2068Crossref PubMed Scopus (668) Google Scholar6904Men and women >50 y with stable coronary artery diseaseTrandolaprilPlacebo9.811.51.717* ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial; ALPINE = Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; CAPPP = Captopril Prevention Project; CHARM = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; HOPE = Heart Outcomes Prevention Evaluation; INVEST = International Verapamil-Trandolapril Study; LIFE = Losartan Intervention for Endpoint Reduction in Hypertension; PEACE = Prevention of Events with Angiotensin Converting Enzyme Inhibition; SOLVD = Studies of Left Ventricular Dysfunction; SR = sustained release; VALUE = Valsartan Antihypertensive Long-term Use Evaluation. Open table in a new tab Several clinical trials demonstrate that ARBs also have beneficial effects on glucose metabolism that likely are independent of bradykinin-mediated mechanisms.34Lindholm LH Ibsen H Borch-Johnsen K LIFE Study Group et al.Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.J Hypertens. 2002; 20: 1879-1886Crossref PubMed Scopus (309) Google Scholar, 35Pfeffer MA Swedberg K Granger CB CHARM Investigators and Committees et al.Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.Lancet. 2003; 362: 759-766Abstract Full Text Full Text PDF PubMed Scopus (1144) Google Scholar, 36Lindholm LH Persson M Alaupovic P Carlberg B Svensson A Samuelsson O Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).J Hypertens. 2003; 21: 1563-1574Crossref PubMed Scopus (283) Google Sch
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