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Blood Pressure or Glycemia Control -- Which Is More
Important in Nephropathy?
1. Blood Pressure
2. Glycemic Control
3. Both
For primary prevention, glycemic control has all the evidence.
Both the Diabetes Control and Complications Trial (DCCT) in type 1[1]
and the United Kingdom Prospective Diabetes Study (UKPDS)[2] in type
2 diabetes showed that intensive vs conventional therapy reduced the
number of patients developing de novo microalbuminuria. After 9 years,
the HbA1c values were 9.1% vs 7.2% in the DCCT and 8.4% vs 7.8% in the
UKPDS. The cumulative incidence of microalbuminuria (defined as an albumin
excretion rate [AER] > 28 micrograms (mcg)/min in the DCCT and an
albumin concentration of > 50 mg/L in the UKPDS) was 34.5% vs 21.4%
and 25.4% vs 19.2% in the DCCT and UKPDS, respectively. These data gave
relative risks for intensive vs conventional of 0.61 (95% confidence
interval [CI] 0.48-0.79) and 0.76 (99% CI 0.62-0.91), respectively.
By contrast, there are no significant data showing that antihypertensive
therapies can prevent microalbuminuria development. Both the EUCLID
(EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes)[3]
and MICROHOPE[4] studies showed a nonsignificant reduction in AER and
albumin/creatinine ratios, respectively.
In terms of secondary prevention of an increase in albuminuria to the
clinically proteinuric range (conventionally an albumin concentration
> 300 mg/L or an AER > 200 mcg/min), the data favor antihypertensive
therapy -- specifically renin-angiotensin blockade using angiotensin
converting-enzyme (ACE) inhibitors in type 1 and angiotensin II receptor
blockers (ARB) in type 2.
A meta-analysis of raw data from over 690 type 1 patients with microalbuminuria
and "normal" blood pressures treated with either an ACE inhibitor
or placebo showed a 75% reduction in AER at 1 year.[5] The odds ratio
(OR) for developing nephropathy was 0.38 for the ACE inhibitor-treated
group, who also had a 3.07 OR for regression to normoalbuminuria. The
IRMA 2 study in 590 type 2 patients with hypertension and microalbuminuria
had a hazard ratio of 0.32 for nephropathy and around 1.6 for normoalbuminuria
for those treated with 300 mg/d irbesartan.[6]
Although early short-term studies from Scandinavia suggested that improved
glycemic control prevented an increase in albuminuria in microalbuminuric
patients, these results were not confirmed by the DCCT[7] or others.[8]
The UKPDS analyzed their data by achieved glycemia[9] and blood pressure.[10]
They found that whereas there was a 37% reduction in microvascular end
points (predominantly retinopathy) for each 1% lowering of HbA1c, the
impact of a 10-mmHg lowering of blood pressure was associated with only
a 13% reduction.
For tertiary prevention, there are no data suggesting that long-term
intensive glycemic control confers benefit. The Collaborative Study
Group Trial of captopril in type 1[11] and irbesartan[12] and losartan[13]
in type 2 nephropathy conclusively showed a reduction in those developing
end-stage renal failure, and these benefits appeared to be renin-angiotensin
system blockade-specific.
What about GFR? Intensive glycemic control can reduce hyperfiltration
in early type 1 diabetes,[14] and glucose-lowering therapy also lowers
GFR in newly diagnosed type 2 patients.[15] The effect of this on long-term
risk for nephropathy development is uncertain. At the stage of microalbuminuria,
glycemic control had little effect on GFR in the DCCT.[7] Antihypertensive
therapy with ACE inhibitors actually reduces GFR in the short term in
microalbuminuric patients,[16] but seems to be associated with a stabilization
thereafter. In the UKPDS, the number of patients doubling baseline serum
creatinine over 12 years was significantly lower in the intensively
managed group. However, the actual numbers affected were only 7 vs 10
(0.91% vs 3.52%).[2] The previously mentioned captopril, irbesartan,
and losartan trials all showed significantly lower percentages of patients
with nephropathy doubling baseline serum creatinine (adjusted risk reductions
49%, 29%, and 25%, respectively).
Finally, the very few biopsy-based studies of renal structure have shown
that pancreas transplantation can prevent glomerulopathy developing
in renal allografts in type 1 diabetic patients,[17] and also a reversal
of lesions in native kidneys after 10 (but not 5) years.[18] Thus, the
lesions may take as long to reverse as they do to develop. The effect
of antihypertensive therapies on structure has only been studied for
a maximum of 3 years, and no significant impact was detected after this
time.[19]
What conclusions can be drawn? First, glycemic control is the only therapy
shown to prevent nephropathy development and is the only treatment proven
to reverse established pathology. By the time AER is in the microalbuminuric
or nephropathic range, only antihypertensive therapy, specifically with
ACE inhibitors or ARB, can slow the pace of progression. However, it
must be remembered that good glycemic control continues to benefit nephropathy
throughout the diabetic patient's life and should be strived for at
all times. Both therapies remain the foundation stones of good care.
The challenge is to optimize them for all patients.
References
1. The Diabetes Control and Complications Research Group. The effect
of intensive treatment of diabetes on the development and progression
of long term complications in insulin dependent diabetes mellitus. N
Engl J Med. 1993; 329:977-986.
2. UKPDS 33. Intensive blood glucose control with sulphonylureas or
insulin compared with conventional treatment and risk of complications
in NIDDM. Lancet. 1998;352:837-852.
3. EUCLID Study Group. Randomized placebo controlled trial of lisinopril
in normotensive patients with insulin dependent diabetes and normoalbuminuria
or microalbuminuria. Lancet. 1997;349:1787-1792.
4. HOPE Study Investigators. Effects of ramipril on cardiovascular and
microvascular outcomes in people with diabetes mellitus: results of
the HOPE and MICROHOPE sub study. Lancet. 2000;355:253-259.
5. Should all patients with type 1 diabetes mellitus and microalbuminuria
receive angiotensin-converting enzyme inhibitors? Ann Intern Med. 2001;134:370-379.
6. Parving HH, Lehnert H, Brochner-Mortensen J, et al The effect of
irbesartan on the development of diabetic nephropathy in patients with
type 2 diabetes. N Engl J Med. 2001;345:870-878.
7. DCCT. Effect of intensive therapy on the prevention and development
of diabetic nephropathy in the diabetes control and complications trial.
Kidney Int. 1995:42:1703-1720.
8. Microalbuminuria Collaborative Study Group UK. Intensive therapy
and progression to clinical albuminuria in patients with insulin dependent
diabetes mellitus and microalbuminuria. BMJ. 1995;311:973-977.
9. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes (UKPDS
35): prospective observational study. BMJ. 2000;321:405-412.
10. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood
pressure with macrovascular and microvascular complications of type
2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.
11. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, et al. The effect of
angiotensin converting enzyme inhibition on diabetic nephropathy. N
Engl J Med. 1993;329:1456-1462.
12. Lewis EJ, Hunsicker LG, Clarke WR, et al. Reno-protective effect
of the angiotensin-receptor antagonist irbesartan in patients with nephropathy
due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
13. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med. 2001;345:861-869.
14. Mogensen CE. Glomerular hyperfiltration in human diabetes. Diabetes
Care. 1994;17:770-775.
15. Vora JP, Dolben J, Williams JD, Peters JR, Owens DR. Impact of initial
treatment on renal function in newly diagnosed type 2 (non insulin dependent)
diabetes mellitus. Diabetologia. 1993;36:734-740.
16. Rossing P. Promotion, prediction and prevention of progression of
nephropathy in type 1 diabetes mellitus. Diabetic Med. 1998;15:900-919.
17. Bilous RW, Mauer SM, Sutherland DE, Najarian JS, Goetz FC, Steffes
MW. The effects of pancreas transplantation on the glomerular structure
of renal allografts in patients with insulin dependent diabetes. N Engl
J Med. 1989;321:80-85.
18. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal
of lesions of diabetic nephropathy after pancreas transplantation. N
Engl J Med. 1998;339:69-75.
19. Baines LA, for the ESPRIT Study Group. Effect of 3 years of antihypertensive
therapy on renal structure in type 1 diabetic patients with albuminuria.
Diabetes. 2001;50:843-850.
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