Hypertension in Diabetics
Part 2

The Drugs

Are ace inhibitors (ACEI) and angiotensin receptor blockers (ARBs) truly better than other agents for the treatment of hypertension in diabetics?

Before we embark on exploring the evidence, let us be perfectly clear. The most important part about treating hypertension, and specifically hypertension in diabetes is to actually treat the blood pressure.

There have been multiple hard end point blood pressure trials published over the last ten years using a variety of agents, a variety of targets, and a variety of inclusion criteria. Most of them have included diabetics as a pre-specified sub-group. In the placebo-controlled trials, the diabetic sub groups have done better under treatment than the general study population, with better relative risk reductions seen in the diabetic sub-groups and lower NNTs. Let us look at 2 classical trials that showed it was important to treat isolated systolic hypertension in the elderly.

The SHEP trial had a total of 4736 men and women sixty years of age or older, with isolated systolic hypertension. This was a placebo-controlled trial in which active treatment consisted of low dose chlorthaladone, a thiazide diuretic, with a step up to atenolol or reserpine. There were 583 Type 2 diabetics in this population. The five year major cardiovascular disease rate was 34% lower for the active treatment group vs placebo for both diabetics and non-diabetics. However, the absolute risk reduction was twice as great for the diabetic as compared to the non-diabetic population. NNT =10 for diabetics, and NNT = 20 for non-diabetics.

Similar effects were seen in Syst-Eur. In this study, the calcium channel blocker nitrendipine was compared to the placebo in the treatment of isolated systolic hypertension. In a post hoc analysis, the treatment effect was compared in diabetic and non-diabetic patients. There were 4695 patients over the age of 60 in this trial with a systolic blood pressure between 160-219, and with a diastolic pressure below 95. Active treatment consisted of nitrendipine 10-40 mg a day with possible addition or substitution of enalapril, (5-20 mg per day) or hydroclorothiazide (12.5-25 mg per day) or both, titrated to reduce the systolic blood pressure by about 20 mm hg or to a target of less than 150. At randomization, 492 patients, or 10.5% of the total were diabetics. Through the median follow-up of two years, systolic and diastolic pressure in the placebo and active treatment groups differed by 8.6mm and 3.9 mm of mercury respectively. Active treatment was found to reduce overall mortality by 55%, (NNT=53 over the 2 years of the study), mortality from cardiovascular disease by 76% and all cardiovascular events combined by 69%. Fatal and non-fatal strokes were reduced by 73%, and all cardiac events combined were reduced by 63% in the group of patients with diabetes. In the non diabetic population the treatment effects were far more modest. Active treatment decreased all cardiovascular events combined by 26% and all strokes by 38%. There was no statistical difference in overall mortality in the non-diabetic study population. Interestingly, 60% of the diabetics were on an ace-inhibitor in this study.

FACET:

This small trial was set up to compare the ace inhibitor fosinopril to the calcium channel blocker amlodipine. The primary aim was to compare the effects of these drugs on serum lipids and diabetes control in Type 2 diabetics with hypertension. (bp>140/90)

ABCD TRIAL:

The results of the ABCD trial have been discussed already. In this earlier sub-study, the CCB nisoldipine was compared with the ACEI enalapril, as a first line anti-hypertensive agent in prevention and progression of diabetic complications In this publication, data on a secondary endpoint, the incidence of myocardial infraction was compared between the two groups. The two groups had similar control of blood pressure, blood glucose, and lipid concentrations. The study found that the CCB was associated with a higher incidence of fatal and non-fatal myocardial infractions. A total of 24 (in 237 patients) in the nisoldipine group versus 4 (in 233 patients) in the Enalapril group. This is a dramatic difference, but again this is a secondary endpoint, which requires confirmation in larger trials.

CAPPP:

The Captopril Prevention Project evaluated the effects of an ace-inhibitor based therapeutic regime on cardiovascular mortality and morbidity in hypertension. There were 10,985 patients in this trial, of which 572, or 4.9%, had diabetes. Patients aged 25-66 years with a diastolic >100 were randomized to receive either captopril or conventional treatment (diuretics and /or beta-blockers). The captopril-based treatment was judged to be equal to a diuretic/ beta-blocker based regime in the large trial. With the diabetics however, the results were quite different. The primary endpoint: fatal and non-fatal myocardial infraction and stroke, as well as cardiovascular death were markedly lower in the captopril group. RRR = 41, P = .018, and NNT = 16 over five years of the study. All cardiac events were lower in the captopril group, but there was no difference in stroke. Total mortality was also significantly reduced by almost 50%. NNT cannot be calculated because the numbers were not presented.

Life Trial:

This was a large trial of 9,193 participants aged 55-80 with essential hypertension (sitting BP 160-200 / 95-115) and LVH as assessed by EKG. A blood pressure lowering regime based on Losartan, an ARB, was compared with a blood pressure regime based on Atenolol, a beta-blocker over 4 years. Blood pressure fell slightly more on the losartan based regime(30.2 / 16.6) vs the atenolol based regime (29.1 / 16.8). There was a small but significant reduction in the primary composite endpoint (death, myocardial infarction and stroke) favoring the losartan group. RRR=13%. NNT=243/year of treatment. The difference was primarily in strokes. The results in diabetics were much more dramatic. 1195 patients were in the diabetic sub-group. The primary composite endpoint was 24% lower in the losartan group. Total mortality was dramatically lower in the losartan group, 11% in the losartan group and 17% in the atenolol group. RRR =40%, P =.001, NNT = 16.6 over six years.

What about ACEI, ARB, and the kidney? Interestingly, although multiple trials have demonstrated the benefit of ace inhibitors in reducing progression to microalbuminuria and reduction of progression of miroalbuminuria, there has been no trial to date on ACE inhibitors demonstrating a reduction of progression to end stage renal disease in patients with diabetes.

Recently two studies have demonstrated a reduction in the rate of progression of nephropathy with ARBs. The RENAAL Study actually demonstrated a reduction of the progression to end stage renal disease (ESRD), as well as showing a reduction in the rate of doubling of baseline serum creatinine concentration with losartan. The IDNT study showed a reduction in the rate of doubling of baseline serum creatinine concentration with irbesartan. Let us look at one of these trials.

RENAAL trial:

A total of 1513 patients were randomized in a double blind fashion to losartan versus placebo, both taken in addition to conventional anti-hypertensive treatment consisting of calcium channel blockers, diuretics, alpha blockers, beta blockers and centrally-acting agents for an average of 3.4 years. The patients were Type 2 diabetics with nephropathy defined as a urinary protein excretion of greater than .5 grams per day, and a creatinine of between 115-265 micromoles/l. The primary endpoint was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death.A total of 327 patients in the losartan group reached a primary endpoint as compared to 359 in the placebo group, a RRR of 16%. Losartan reduced the incidents of doubling of serum creatinine by 25%, and endstage renal disease by 28%. Interestingly, there was no difference in the death rate between the two groups. The benefits exceeded that attributed to changes in blood pressure.

As we have demonstrated ACEI and ARB based regimes are particularly effective in diabetic hypertensives. Can we combine both agents in an individual patient? This was looked at in the CALM study:

CALM Trial:

This was a prospective randomized parallel group, double blind study involving 199 Type 2 diabetics aged 30-75, with previously diagnosed hypertension and microalbuminuria. Patients got monotherapy with candesartan, an ARB, or lisinopril, an ACEI, or a combination of both the drugs over 24 weeks. What it basically demonstrated was systolic blood pressure and diastolic blood pressures were further reduced on a combination of an ACE inhibitor and an ARB. Microalbuminuria was also further reduced with dual blockade of the renin angiotensin system. This study was not powered, nor did it last long enough to look at any hard endpoints.

So what have we learned after reviewing all these studies? The target for blood pressure in diabetes should be less than 130/80. Ace inhibitors and ARBs are the preferred first line agents, but multiple drugs are going to be needed to reach targets and drugs from any class can be used. This is just what the guidelines say. An additional interesting finding in multiple trials such as HOPE, CAPPP and LIFE has been a decrease of new onset diabetes in the groups exposed to ACEI and ARBs compared to the comparator group in these trails.

- Farokh Buhariwalla

Thanks to Dr. Hector Baillie for reviewing the draft copy of this article. Dr. Baillie is a graduate of University of Glasgow, Scotland. He has spent 16 years in community based IM practice in British Columbia and is currently Secretary of the Canadian Society of Internal Medicine and examiner for the RCPSC.

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You can search for abstracts of the above references by following this link: PubMed