Table II.
Randomized Double‐Blind Clinical Trials Assessing the Effects of Inhibition of the Renin‐Angiotensin System on Risk of NOD
| Study | Patient Population | Intervention a | Prespecified End Point? | Results |
|---|---|---|---|---|
| ACE inhibitors | ||||
| HOPE 33 | 9297 patients with history of CAD, stroke, PVD, or diabetes and ≥1 other CVD risk factor | Ramipril (up to 10 mg/d) or placebo for 5.0 years | Yes | 34% reduction in risk of NOD with ramipril vs placebo (RR, 0.66; 95% CI, 0.51–0.85; P<.001) |
| ALLHAT 34 | 33,357 hypertensive patients with ≥1 other CVD risk factor and no history of hospitalization or treatment for symptomatic HF or LVEF <35% | Chlorthalidone (12.5–25 mg/d), amlodipine (2.5–10 mg/d), or lisinopril (10–40 mg/d) for 4.9 years | No | Incidence of NOD at 4 years was 11.6% in the chlorthalidone group, 9.8% in the amlodipine group (P=0.4 vs chlorthalidone), and 8.1% in the lisinopril group (P<.001 vs chlorthalidone) |
| PEACE 35 | 8290 with stable CAD and normal or slightly reduced left ventricular function | Trandolapril (2–4 mg/d) or placebo for 4.8 years (median) | No | 17% reduction in risk of NOD with trandolapril vs placebo (RR, 0.83; 95% CI, 0.72–0.96; P=.001) |
| ASCOT‐BPLA 36 | 19,257 hypertensive patients with ≥3 other CVD risk factors and no history of MI, currently treated angina, cerebrovascular event within 3 months, or uncontrolled arrhythmias | Amlodipine (5–10 mg/d) (± perindopril [4–8 mg/d]) or atenolol (50–100 mg/d) (± bendroflumethiazide [1.25–2.5 mg/d]) for 5.5 years (median) | Yes | 30% reduction in risk of NOD with amlodipine (± perindopril) vs atenolol (± diuretic) (RR, 0.70; 95% CI, 0.63–0.78; P<.0001) |
| DREAM 37 | 5269 patients with IFG and/or IGT but without CVD or renal disease | Ramipril (up to 15 mg/d) or placebo for 3.0 years (median) | Yes | NOD developed in 17.1% of patients in the ramipril group and 18.5% in the placebo group (RR, 0.91; 95% CI, 0.80–1.03; P=NS); reversion to normoglycemia in 42.5% of ramipril group vs 32.2% of placebo group (RR, 1.16; 95% CI, 1.07–1.27; P=.001) |
| ARBs | ||||
| LIFE 38 | 9193 hypertensive patients with LVH without MI or stroke within 6 months, HF or LVEF ≤40% | Losartan (50–100 mg/d) (± HCTZ [12.5–25 mg/d]) or atenolol (50–100 mg/d) (± HCTZ [12.5–25 mg/d]) for 4.8 years | Yes | 25% reduction in risk of NOD with losartan vs atenolol (RR, 0.75; 95% CI, 0.63–0.86; P=.001) |
| SCOPE 39 | 4964 hypertensive patients aged 70–89 years without MI or stroke within 6 months or decompensated HF | Candesartan (8–16 mg/d) or placebo/other drugs for 3.7 years | No | 19% reduction in risk of NOD with candesartan vs placebo (RR, 0.81; 95% CI, 0.61–1.02; P=.09) |
| CHARM 40 | 7599 patients with HF (LVEF ≤40%) | Candesartan (4–32 mg/d) or placebo for 3.1 years | Yes | 22% reduction in risk of NOD with candesartan vs placebo (RR, 0.78; 95% CI, 0.64–0.96; P=.02) |
| VALUE 41 | 15,245 hypertensive patients with high risk of CVD events without history of MI or severe renal disease | Valsartan (80–160 mg/d) (± HCTZ [12.5–25 mg/d]) or amlodipine (5–10 mg/d) (± HCTZ [12.5–25 mg/d]) for 4.2 years | Yes | 23% reduction in risk of NOD with valsartan vs amlodipine (RR, 0.77; 95% CI, 0.69–0.86; P<.0001) |
| TRANSCEND 41 | 5926 patients intolerant to ACE inhibitors with CAD, PVD, CBVD, or diabetes with end organ damage | Telmisartan (80 mg/d) or placebo for 4.7 years (median) | Yes | 15% reduction in risk of NOD with telmisartan vs placebo (RR, 0.85; 95% CI, 0.71–1.02; P=.081) |
| ACE inhibitor/ARB combination | ||||
| ONTARGET 43 | 25,620 patients with CAD, PVD, CBVD, or diabetes with end organ damage | Ramipril (10 mg/d), telmisartan (80 mg/d), or ramipril (10 mg/d) + telmisartan (80 mg/d) for 4.7 years (median) | Yes | 12% increase in risk of NOD with telmisartan vs ramipril (RR, 1.12; 95% CI, 0.97–1.29; P=NS); 9% reduction in risk of NOD with ramipril + telmisartan vs ramipril (RR, 0.91; 95% CI, 0.78–1.06; P=NS) |
Abbreviations: ACE, angiotensin‐converting enzyme; ALLHAT, Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial; ARB, angiotensin II receptor blocker; ASCOT‐BPLA, Anglo‐Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; CAD, coronary artery disease; CBVD, cerebrovascular disease; CHARM, Candesartan in Heart failure–Assessment of Reduction in Morbidity and Mortality; CI, confidence interval; CVD, cardiovascular disease; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; HCTZ, hydrochlorothiazide; HF, heart failure; HOPE, Heart Outcomes Prevention Evaluation; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LIFE, Losartan Intervention for End Point Reduction in Hypertension; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; MI, myocardial infarction; NOD, new‐onset diabetes; NS, not significant; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; PEACE, Prevention of Events With Angiotensin‐Converting Enzyme Inhibition; PVD, peripheral vascular disease; RR, relative risk; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE‐Intolerant Subjects With Cardiovascular Disease; VALUE, Valsartan Long‐term Use Evaluation. aMean years of follow‐up unless indicated.