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Which is better to treat hypertension in patients with
diabetes?
1. Ace Inhibitors
2. Calcium Channel Blockers
3. Thiazide Diuretic + Beta Blocker
4. An ARB
5. Any of the Above
The correct answer is 5, any of the above. There is no one product
that works for everyone, In hypertensive diabetic patients, lower the
blood pressure to target by any means, but choose a combination that
best suits the individual patient.
This is a 2-part question that addresses the treatment of hypertension
and the prevention of renal disease. Numerous recent studies have shown
that lowering blood pressure reduces cardiovascular morbidity and mortality
in human diabetes.[1] There does not appear to be any lower limit of
blood pressure at which benefit is not seen. The Hypertension Optimal
Treatment (HOT) study[2] showed continuing benefit with diastolic pressures
lowered to 80 mm Hg. The importance of systolic hypertension has become
more apparent lately and recommended blood pressure targets of 130/85
mm Hg or 140/80 mm Hg have been proposed by the World Health Organization
(WHO)[1] and British Hypertension Society,[3] respectively.
To date, there appears to be no benefit of one class of agent over another.
Older drugs, such as thiazides and beta-blockers, are as effective as
newer agents.[1] Low-dose thiazides (eg, bendroflumethiazide 2.5mg,
hydrochlorothiazide and chlorthalidone 12.5mg) seem metabolically safe
in diabetes. Beta-blockers may promote glucose intolerance however and
seem less well tolerated than ACE inhibitors, at least in 1 study.[4]
However, they are probably more effective postmyocardial infarction
in diabetic than in nondiabetic subjects. The concern about dihydropyridine
calcium channel blockers following results from Appropriate Blood Pressure
Control in Diabetes (ABCD)[5] study and Fosinopril versus Amlodipine
Cardiovascular Events Trial (FACET)[6] does not seem justified since
the publication of results from Systolic Hypertension in Europe (SystEur)[7]
and HOT. Doxazosin monotherapy should be used with caution however following
the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
(ALLHAT) study decision to withdraw it.[8]
Results from the recently published Heart Outcomes Prevention Evaluation
(HOPE) and MICRO-HOPE Study[9] suggest a benefit of ramipril in reducing
cardiovascular morbidity and mortality in high-risk type-2 diabetic
patients, two thirds of whom were said to be hypertensive. However,
no data on concomitant therapies are given and the added risk of hypertension
alone may not be that strong.
Thus, the important message is that in hypertensive diabetic patients,
lower the blood pressure to target by any means, but choose a combination
that best suits the individual patient.
The prevention of renal disease is more difficult to answer in some
ways but easier in others. The difficult part is that few studies have
used hard end points, such as renal failure or reduction in glomerular
filtration rate. Most have reported an effect on proteinuria or albuminuria
and used this as a surrogate. It is still not clear whether reduced
proteinuria equates to renal functional preservation in human diabetes.
Moreover, in many studies, it has been difficult to dissociate benefits
in terms of reduction of proteinuria as being due to particular agents
or to concomitant reduction in blood pressure. The easy part of the
answer is that, for the most part, ACE inhibitors show a greater propensity
to lower albuminuria than other agents.
Primary prevention in the context of albuminuria would mean prevention
into the microalbuminuric range (20-200mcg/min or 30-300mg/d). Some
studies using ACE inhibitors in type-1 patients have demonstrated such
an effect but data in type-2 patients are more scarce.[10]
Secondary prevention could be defined as a reduction in the numbers
of patients progressing to clinical nephropathy (albuminuria > 300
mg/d) and many studies in microalbuminuric type 1 and 2 patients with
and without hypertension have shown that ACE inhibitors are effective
in this regard.[11,12] There are also data showing that beta-blockers
and calcium channel blockers are also effective in this regard, but
on balance the degree of reduction of albuminuria is less.[11,12]
Only 1 study has shown a benefit of ACE inhibitors on the development
of end-stage renal disease, the Collaborative Study Group Trial in proteinuric
type-1 patients.[13] This could be considered to be evidence of tertiary
prevention. Two large studies in type-2 patients with nephropathy that
are comparing angiotensin II receptor antagonists and calcium channel
blockers are due to report next year.
In terms of preventing renal disease, most endo’s probably use
ACE inhibitors as first-line treatment in patients with type 1 or type
2 diabetes who have increased albuminuria regardless of their blood
pressure; although in practice, many will be hypertensive by modern
definitions.[1,3] Whether these drugs should be used in normoalbuminuric
and normotensive subjects is a hotly debated topic. As a final point,
it important to mention that increased albuminuria is often associated
with other cardiovascular risk factors including hyperlipidemia and
smoking. These will also need vigorous correction.
References
1. Guidelines Subcommittee. 1999 World Health Organization -- International
Society of Hypertension Guidelines for the Management of Hypertension.
J Hypertens. 1999;17:151-183.
2. Hansson L, Zanchetti A, Caruthers SG, et al for the HOT Study Group.
Effects of intensive blood pressure lowering and low dose aspirin in
patients with hypertension: principle results of the Hypertension Optimal
Treatment (HOT) randomised Trial. Lancet 1998;351:1755-1762.
3. Ramsay LE, Williams B, Johnston GD, et al. British Hypertension Society
Guidelines for Hypertension Management. Brit Med J. 1999;319:630-635.
4. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril
in reducing risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 39. Brit Med J. 1998;317: 713-720.
5. Estacio RO, Raymond OE, Jeffers BW, et al. The effect of nisoldipine
as compared with enalapril on cardiovascular outcomes in patients with
NIDDM and hypertension. N Engl J Med. 1998;338:645-652.
6. Tatti P, Pahor M, Byington R, et al. Outcome results of the Fosinopril
vs Amlodipine Cardiovascular Events randomised Trial (FACET) in patients
with hypertension and NIDDM. Diabetes Care. 1998;21:597-603.
7. Staessen JA, Fagard R, Thijs L, et al. For the Systolic Hypertension
in Europe (SystEur) Trial investigators. Randomised double-blind comparison
of placebo and active treatment for older patients with isolated systolic
hypertension. Lancet. 1997;350:757-764.
8. Lasagna L. Diuretics vs alpha-blockers for treatment of hypertension:
lessons from ALLHAT. Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial. JAMA. 2000;283:2013-2014
9. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators.
Effects of ramipril on cardiovascular and microvascular outcomes in
people with diabetes mellitus: results of the HOPE Study and MICRO-HOPE
Sub-study. Lancet. 2000;355:253-259.
10. The EUCLID Study Group. Randomised placebo-controlled trial of lisinopril
in normotensive patients with insulin-dependent diabetes and normoalbuminuria
or microalbuminuria. Lancet. 1997;349:1787-1792.
11. Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of anti-hypertensive
therapy on the kidney in patients with diabetes: a meta-regression analysis.
Ann Intern Med. 1993;118:129-138.
12. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different
antihypertensive drugs in human diabetic nephropathy: an updated meta-analysis.
Nephrol Dial Transplant 1995;10:39-45.
13. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme
inhibition on diabetic nephropathy. The Collaborative Study Group. N
Engl J Med. 1993;329:1456-1462.
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