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Table 2—

Randomized controlled trials

StudyPopulation (age)*Definition of type 2 diabetesMean follow-up (years)/(rate)Incidence of type 2 diabetes RR (95% CI)Major limitations
ALLHAT (21) 14,816 hypertensive patients from North America at high cardiovascular risk (≥55 years) (reserpine, clonidine and/or hydralazine were add-on therapy) FPG ≥7.0 mmol/l 4 (38%) Amlodipine (9.8) vs. chlorthalidone (11.6%): 0.80 (0.64–0.99); lisinopril (8.1) vs. chlorthalidone (11.6%): rr 0.70 (0.56–0.86) 1) Post hoc analysis; 2) of those that had a baseline FPG; measurement, only 38% had a repeat measurement at 4 years 
ALPINE (22) 392 hypertensive patients from Sweden (mean age 55 years) Physician-reported or prescription of diabetes medication or two FPG levels ≥7 mmol/l. Predefined end point 1 (100%) Candesartan ± felodipine (0.5) vs. HCTZ ± atenolol (4.1%): 0.13 (0.02–0.99) 1) Low number of type 2 diabetes case subjects (nine total) resulting in wide CIs 
CAPPP (23) 10,413 hypertensive patients from Sweden and Finland (25–66 years) (diuretics were second-line therapy in the ACE inhibitor arm and CCBs were add-on therapy in both arms) Two FPG levels ≥6.7 mmol/l (predefined end point) 6.1 (100%) Captopril (6.5) vs. BB/thiazides (7.2%): 0.86 (0.74–0.99) from intention-to-treat analysis; 0.79 (0.67–0.94) from on-treatment analysis 1) Open-label design; 2) add-on therapy in the ACE inhibitor group was a diuretic, which may have contaminated results; 3) relative proportions of patients on BB and thiazide therapy not given 
CHARM (24) 5,439 patients with symptomatic heart failure (≥18 years) Not specified (predefined end point) 3.1 (100%) Candesartan (6) vs. placebo (7%): 0.78 (0.64–0.96)  
EWPHE (25) 840 patients enrolled in trial (≥60 years) (on-treatment analysis) Physician reported 4.7 (85%) Triamterene plus HCTZ ± methyldopa (7.0) vs. placebo (4.7%): 1.5 (0.85–2.6) 1) Post hoc analysis; 2) diagnosis depended on physician reporting; 3) small sample size 
HAPPHY (26) 6,569 caucasian men enrolled in the trial (40–64 years) (hydralazine and spironolactone were second-line agents) FPG >6.8 mmol/l and two positive urine dipsticks for glucosuria 3.8 (98%) Thiazides (2.3) vs. BB (2.6%): 0.88 (0.65–1.19) 1) Open-label design; 2) 4% of patients were on both thiazides and BB; 3) post hoc analysis 
HOPE (27) 5,720 patients from 19 countries at high cardiovascular risk (≥55 years) Patient self reported 4.5 (99%) Ramipril (3.6) vs. placebo (5.4%): 0.66 (0.51–0.85) 1) Diabetes not a predefined end point; 2) type 2 diabetes was self-reported 
INSIGHT (28) 5,019 hypertensive patients from Europe and Israel with at least one additional cardiovascular risk factor (55–80 years) (atenolol or enalapril were second-line agents) RPG >11.0 mmol/l or use of antidiabetic medication. Prespecified end point 3 (98%) Nifedipine (4.3) vs. HCTZ/amiloride (5.6%): 0.77 (0.62–0.96) 1) Relative percentage of patients on BBs and ACE inhibitors as second-line therapy in both study arms not stated 
LIFE (29) 7,998 hypertensive patients from the U.S. and Europe with left ventricular hypertrophy (55–80 years); (thiazides were the preferred second-line agent) 2 FPG levels ≥6.7 mmol/l. Prespecified end point 4.8 (99%) Losartan (6) vs. atenolol (8%): 0.75 (0.63–0.88) 1) Results may represent a beneficial effect of losartan, a deleterious effect of atenolol, or both; 2) relative frequency of thiazide use in each study arm not given 
NORDIL (30) 10,154 hypertensive patients from Norway and Sweden (50–69 years) (ACE inhibitors or angiotension receptor blockers were add-on therapy in 25% of each study arm) Exact criteria not specified (predefined end point) 4.5 (99%) Diltiazem (4) vs. diuretics/BB (5%): 0.87 (0.73–1.04) 1) Open-label design (possible detection bias); 2) second-line agents were drugs from other study arms (contamination) 
SCOPE (31) 4,342 hypertensive patients with mild to moderate hypertension (70–89 years) (thiazides/BB were common second-line agents) Not specified (predefined end points) 3.7 (100%) Candesartan (4.3) vs. placebo (5.3%): 0.81 (0.62–1.06) 1) 84% of patients in the placebo group and 75% of patients in the candesartan group were on additional agents 
SHEP (33) 4,153 subjects from the U.S. with isolated systolic hypertension (≥60 years) (reserpine was an additional second-line agent) Self-reported or FPG ≥7.8 mmol/l or on antidiabetic medication 3 (not reported) Chorthalidone ± atenolol (8.6) vs. placebo (7.5%): 1.2 (0.9–1.5) 1) 33% of participants in the placebo arm were on active antihypertensive therapy at the end of the study; 2) post hoc analysis 
STOP-2 (32) 5,893 hypertensive patients from Sweden (70–84 years) Two FPG levels ≥6.7 mmol/l (predefined end points) 4 (100%) ACE inhibitors vs. diuretics/BB: 0.96 (0.72–1.27); CCB vs. diuretics/BB: 0.97 (0.73–1.29); ACE inhibitors vs. CCB: 0.96 (0.74–1.31)§ 1) Open-label design; 2) second-line agents were drugs from other study arms (contamination) 
Vermes et al (34) 311 patients with left ventricular dysfunction from Canada (<80 years) (local center of SOLVD trial) FPG ≥7 mmol/l on two occasions 2.9 (94%) Enalapril (6) vs. placebo (22%): 0.26 (0.13–0.53) 1) Post hoc analysis of a single study center; 2) small sample size 
StudyPopulation (age)*Definition of type 2 diabetesMean follow-up (years)/(rate)Incidence of type 2 diabetes RR (95% CI)Major limitations
ALLHAT (21) 14,816 hypertensive patients from North America at high cardiovascular risk (≥55 years) (reserpine, clonidine and/or hydralazine were add-on therapy) FPG ≥7.0 mmol/l 4 (38%) Amlodipine (9.8) vs. chlorthalidone (11.6%): 0.80 (0.64–0.99); lisinopril (8.1) vs. chlorthalidone (11.6%): rr 0.70 (0.56–0.86) 1) Post hoc analysis; 2) of those that had a baseline FPG; measurement, only 38% had a repeat measurement at 4 years 
ALPINE (22) 392 hypertensive patients from Sweden (mean age 55 years) Physician-reported or prescription of diabetes medication or two FPG levels ≥7 mmol/l. Predefined end point 1 (100%) Candesartan ± felodipine (0.5) vs. HCTZ ± atenolol (4.1%): 0.13 (0.02–0.99) 1) Low number of type 2 diabetes case subjects (nine total) resulting in wide CIs 
CAPPP (23) 10,413 hypertensive patients from Sweden and Finland (25–66 years) (diuretics were second-line therapy in the ACE inhibitor arm and CCBs were add-on therapy in both arms) Two FPG levels ≥6.7 mmol/l (predefined end point) 6.1 (100%) Captopril (6.5) vs. BB/thiazides (7.2%): 0.86 (0.74–0.99) from intention-to-treat analysis; 0.79 (0.67–0.94) from on-treatment analysis 1) Open-label design; 2) add-on therapy in the ACE inhibitor group was a diuretic, which may have contaminated results; 3) relative proportions of patients on BB and thiazide therapy not given 
CHARM (24) 5,439 patients with symptomatic heart failure (≥18 years) Not specified (predefined end point) 3.1 (100%) Candesartan (6) vs. placebo (7%): 0.78 (0.64–0.96)  
EWPHE (25) 840 patients enrolled in trial (≥60 years) (on-treatment analysis) Physician reported 4.7 (85%) Triamterene plus HCTZ ± methyldopa (7.0) vs. placebo (4.7%): 1.5 (0.85–2.6) 1) Post hoc analysis; 2) diagnosis depended on physician reporting; 3) small sample size 
HAPPHY (26) 6,569 caucasian men enrolled in the trial (40–64 years) (hydralazine and spironolactone were second-line agents) FPG >6.8 mmol/l and two positive urine dipsticks for glucosuria 3.8 (98%) Thiazides (2.3) vs. BB (2.6%): 0.88 (0.65–1.19) 1) Open-label design; 2) 4% of patients were on both thiazides and BB; 3) post hoc analysis 
HOPE (27) 5,720 patients from 19 countries at high cardiovascular risk (≥55 years) Patient self reported 4.5 (99%) Ramipril (3.6) vs. placebo (5.4%): 0.66 (0.51–0.85) 1) Diabetes not a predefined end point; 2) type 2 diabetes was self-reported 
INSIGHT (28) 5,019 hypertensive patients from Europe and Israel with at least one additional cardiovascular risk factor (55–80 years) (atenolol or enalapril were second-line agents) RPG >11.0 mmol/l or use of antidiabetic medication. Prespecified end point 3 (98%) Nifedipine (4.3) vs. HCTZ/amiloride (5.6%): 0.77 (0.62–0.96) 1) Relative percentage of patients on BBs and ACE inhibitors as second-line therapy in both study arms not stated 
LIFE (29) 7,998 hypertensive patients from the U.S. and Europe with left ventricular hypertrophy (55–80 years); (thiazides were the preferred second-line agent) 2 FPG levels ≥6.7 mmol/l. Prespecified end point 4.8 (99%) Losartan (6) vs. atenolol (8%): 0.75 (0.63–0.88) 1) Results may represent a beneficial effect of losartan, a deleterious effect of atenolol, or both; 2) relative frequency of thiazide use in each study arm not given 
NORDIL (30) 10,154 hypertensive patients from Norway and Sweden (50–69 years) (ACE inhibitors or angiotension receptor blockers were add-on therapy in 25% of each study arm) Exact criteria not specified (predefined end point) 4.5 (99%) Diltiazem (4) vs. diuretics/BB (5%): 0.87 (0.73–1.04) 1) Open-label design (possible detection bias); 2) second-line agents were drugs from other study arms (contamination) 
SCOPE (31) 4,342 hypertensive patients with mild to moderate hypertension (70–89 years) (thiazides/BB were common second-line agents) Not specified (predefined end points) 3.7 (100%) Candesartan (4.3) vs. placebo (5.3%): 0.81 (0.62–1.06) 1) 84% of patients in the placebo group and 75% of patients in the candesartan group were on additional agents 
SHEP (33) 4,153 subjects from the U.S. with isolated systolic hypertension (≥60 years) (reserpine was an additional second-line agent) Self-reported or FPG ≥7.8 mmol/l or on antidiabetic medication 3 (not reported) Chorthalidone ± atenolol (8.6) vs. placebo (7.5%): 1.2 (0.9–1.5) 1) 33% of participants in the placebo arm were on active antihypertensive therapy at the end of the study; 2) post hoc analysis 
STOP-2 (32) 5,893 hypertensive patients from Sweden (70–84 years) Two FPG levels ≥6.7 mmol/l (predefined end points) 4 (100%) ACE inhibitors vs. diuretics/BB: 0.96 (0.72–1.27); CCB vs. diuretics/BB: 0.97 (0.73–1.29); ACE inhibitors vs. CCB: 0.96 (0.74–1.31)§ 1) Open-label design; 2) second-line agents were drugs from other study arms (contamination) 
Vermes et al (34) 311 patients with left ventricular dysfunction from Canada (<80 years) (local center of SOLVD trial) FPG ≥7 mmol/l on two occasions 2.9 (94%) Enalapril (6) vs. placebo (22%): 0.26 (0.13–0.53) 1) Post hoc analysis of a single study center; 2) small sample size 
*

Patients with diabetes at baseline are not included in the sample sizes reported.

Refers to the percentage of patients with complete follow-up.

RRs and CIs calculated from the data presented or obtained from study authors.

§

Incidence rates of type 2 diabetes not provided in STOP-2. BB, β-blockers; CCB, calcium channel blockers.

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