Choice of Antihypertensive Drug in the Diabetic Patient from Prognostic Point of View

A meta-analysis 13 evaluating the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents (diuretics, beta blockers, calcium channel blockers) in people with diabetes. 19 randomized controlled trials (RCTs) with 25 414 participants were included. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% CI 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22).

A meta-analysis 1 included 9 randomized clinical trials on the treatment of hypertension aiming at primary prevention and including diabetic patients (n=27 743).

Diuretics vs. beta blockers

• A meta-analysis 2 compared the results from four placebo-controlled trials of the treatment of hypertension (EWPHE, SHEP, STOP-H, HDFP) with diuretics or beta-blockers as the first-line drugs for diabetic patients. Analysis showed that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion could be drawn for beta-blockers, owing to the small sample size.

Diuretics/beta blockers vs. ACE inhibitors

• In the UKPDS study 3, a subgroup comparison between patients receiving either captopril or atenolol was performed within the group receiving intensified treatment. No differences in the outcome measures were observed.
• The Swedish-Finnish Captopril Prevention Project study (CAPPP) 4 compared the effects of ACE inhibition with captopril to conventional therapy (beta blocker or diuretic) on cardiovascular morbidity and mortality in patients with hypertension. In the whole study population, both treatments were equally effective in reducing the risk of cardiovascular morbidity and mortality during the six-year follow-up. 572 subjects had diabetes at the baseline, and for them, the target was to lower diastolic blood pressure below 90 mmHg. The rate of cardiovascular events was 3-to-4-fold in the diabetic subjects as compared to non-diabetics. The rate reduction in the group receiving captopril was 41% for all cardiovascular events, 66% for myocardial infarction, 46% for all cause mortality, and 52% for cardiovascular mortality as compared to the group receiving conventional treatment.
• In the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study 5 with elderly participants (aged 70-84 years) all treatment options (beta blocker and/or diuretic, calcium channel blocker, ACE inhibitor) were equally effective in prevention of cardiovascular mortality or major events also in hypertensive patients with diabetes.

Calcium channel blockers vs. ACE inhibitors

• The Appropriate Blood Pressure Control in Diabetes study (ABCD) 6 7 compared the calcium channel blocker nisoldipine with enalapril. In the first subgroup analysis of 470 hypertensive patients reporting the 5 year incidence of myocardial infarction 6, nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total 4; risk ratio 9.5; 95 percent confidence interval 2.7 to 33.8). A later analysis 7 did not report any difference in mortality between the groups and neither was there any difference in the clinical subgroups of fatal events.
• In the European Fosinopril versus Amlodipine Cardiovascular Events Randomised Trial (FACET) study 8 with a total of 380 hypertensive diabetics, those using an ACE-inhibitor (fosinopril) were shown to have a 51% lower risk of major vascular events as compared with patients using amlodipine. The study has been heavily criticized for methodological weaknesses.
• In the STOP-2 trial 5, treatment with a calcium channel blocker was as effective as with an ACE inhibitor in preventing cardiovascular events. However, ACE inhibitors were more effective in reducing coronary events and heart failure.

Beta-blockers/diuretics vs. calcium channel blockers

• In the Swedish STOP-2 trial, treatment with a calcium channel blocker was as effective as treatment with a beta-blocker/diuretic or an ACE inhibitor in preventing cardiovascular events even in hypertensive patients with diabetes. Respectively, treatment with a calcium channel blocker was as effective as treatment with a diuretic/beta-blocker in the Nordic Diltiazem study 9.

ACE inhibitors in high risk patients

• The position of ACE inhibitors was further strengthened by the results of the Heart Outcomes Prevention Ecaluation (HOPE) study (MICRO-HOPE) 10. The basic question was wether an ACE inhibitor (ramipril) would improve the prognosis in high risk patients. The study was the first in its class. The total number of participants in the study was nearly 10 000, of whom approximately one third had diabetes. In addition to diabetes, the participants had to have one of the following risk factors: a history of a cardiovascular disease (coronary heart disease, stroke or peripheral vascular disease), elevated blood pressure or drug treatment for hypertension, smoking, microalbuminuria, serum cholesterol> 5.2 mmol/l or HDL-cholesterol< 0.9 mmol/l. Patients with a low ejection fraction (< 40%) or heart failure were excluded. The patients were randomized to receive either placebo or ramipril, with a target dose of 10 mg. Mean age was 66 years, with 27% women. It should be noted, that less than half of the patients were hypertensive (58% and 54% in the treatment and placebo groups, respectively), and the baseline level of blood pressure was 141.7/80 and 142.3/79.3 mmHg. In the ramipril group, systolic blood pressure was lowered by 1.9 mmHg and diastolic pressure by 3.3 mmHg. In spite of the small reduction in blood pressure in the diabetic patients, the primary outcome measure, the risk of combined cardiovascular morbidity, was lowered by 25% (277 vs. 351 events, p=0.002). Also total mortality was reduced by 24% (196 vs. 248 events, p=0.004).

Conclusions:Thiazide diuretics have a clear status in the treatment of elevated blood pressure in patients with diabetes. In the primary prevention, a strategy based on beta-blockers only is not as clear. However, based on the results from the UKPDS study and on the evidence from the treatment of coronary artery disease manifestations, beta-blockers combined with diuretics may be considered as one of the first-line options in the treatment. It is probably reasonable to recommend beta1-selective beta-blockers to patients with diabetes. The conventional treatment with diuretics and beta-blockers appears to be as effective as treatment with ACE inhibitors considering cardiovascular morbidity, but further research on the topic is needed. The HOPE study with high-risk patients was actually not a study on the treatment of elevated blood pressure, because hypertensive diabetics were not randomized separately, and the results were probably not due to the lowering of elevated blood pressure as such. However, the results support the use of an ACE inhibitor (ramipril) for high risk patients, even if it remains open whether other ACE inhibitors (class or ramipril effect) or other antihypertensive drugs would elicit similar benefits in a similar study design.

Thus, the target level of blood pressure is essential in the treatment of patients with diabetes. To reach the target, a combination of several preparations is required. A reduction in the rate of cardiovascular events has been achieved with strategies based on thiazide diuretics, beta-blockers, calcium channel blockers and ACE inhibitors, but in the treatment of diabetic patients, issues related to compliance, co-morbidity and economic questions should also be considered. Studies comparing different preparations and also including considerable numbers of diabetic patients will be published in the next few years.

Evidence on the effect of angiotensin receptor blockers on the clinical outcome events is also gathering. In the LIFE study 11, 9 193 participants aged 55-80 years with essential hypertension and LVH ascertained by ECG were randomized to either losartan-based or atenolol-based antihypertensive treatment in a blinded fashion. In both groups, first 12.5 mg hydrochlorothiazide and then, if necessary, a third antihypertensive agent may have been added to the treatment in order to reach the target blood pressure level of 140/90 mmHg. At the end of the study, 73-77% of the participants used the trial medication. All in all, only 15% of the patients using the trial medication used losartan or atenolol as monotherapy. The baseline blood pressure was 174(14) / 98(9) mmHg. The blood pressure fell by 30.2/16.6 mmHg in the losartan group and by 29.1/16.8 mmHg in the atenolol group.

The primary end points included non-fatal myocardial infarction and non-fatal stroke, and mortality in myocardial infarction, stroke, sudden death, heart failure or other disease of cardiovascular origin. Losartan reduced the risk of primary endpoint events in the whole study population by 13% as compared to atenolol (p=0.021) and by 24% in diabetics (n=1 195; p=0.031) 12. In the whole population, the difference was mainly explained by the lower risk of stroke, and in the diabetics by the lower risk of cardiovascular mortality. In the diabetic participants, the risk of other than cardiovascular mortality was 42% lower than in the atenolol group. Losartan reduced the risk of diabetes onset by 25% (p=0.001) as compared to atenolol.

A Systematic Review 14 comparing the safety and efficacy between ACEi and ARB on the management of hypertension included 10 articles with a total of 1 621 445 patients. Both ACEIs and ARBs were similar in their efficacy in lowering blood pressure. However, ACEi was revealed to be superior to ARB in reducing cardiovascular events and all-cause mortality. ARB was shown to be better tolerated by patients than ACEi.

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