Effects of Angiotensin-Effects of Angiotensin-Converting- Enzyme inhibitors Converting- Enzyme inhibitors on nephropathy outcomes in on nephropathy outcomes in

patients with patients with type 1 diabetestype 1 diabetes

K.Ounaissa, H.Jammoussi, A.Kacem, K.Ounaissa, H.Jammoussi, A.Kacem, Ch.Amrouche, I.Ben Ahmed, O.Berriche, Ch.Amrouche, I.Ben Ahmed, O.Berriche,

S.Blouza.S.Blouza.

NATIONAL INSTITUTE OF NUTRITION, TUNIS –TUNISIA10th meeting of MGSD, Turkey, 26 – 29 April 2007

IntroductionIntroduction• Diabetic nephropathy is the most common cause for Diabetic nephropathy is the most common cause for

end-stage renal disease (ESRD).end-stage renal disease (ESRD).• It occurs in ~ 30 % of people with type 1 diabetesIt occurs in ~ 30 % of people with type 1 diabetes 25 – 40 % type 2 diabetes25 – 40 % type 2 diabetes• Risk factors include hyperglycemia, hypertension, Risk factors include hyperglycemia, hypertension,

genetic predisposition, albuminuria,…genetic predisposition, albuminuria,…• Early identification of patients who are at high risk is Early identification of patients who are at high risk is

mandatory in order to prevent the development or mandatory in order to prevent the development or progression of diabetic kidney injury. progression of diabetic kidney injury.

• MicroalbuminuriaMicroalbuminuria is the earliest marker, is the earliest marker, predicts progressive diabetic predicts progressive diabetic nephropathynephropathy (80 % of type 1 diabetics progress to overt nephropathy over a (80 % of type 1 diabetics progress to overt nephropathy over a period of 10 – 15 years, GFR gradually falls, ESDR develops in 50 % within 10 years period of 10 – 15 years, GFR gradually falls, ESDR develops in 50 % within 10 years and > 75 % by 20 years) and > 75 % by 20 years)

and cardiovascular diseases (endothelium dysfunction.and cardiovascular diseases (endothelium dysfunction.

• Necessity of specific interventions :Necessity of specific interventions : - - optimization of glucose control (DCCT, UKPDS)optimization of glucose control (DCCT, UKPDS) - optimization of blood pressure control- optimization of blood pressure control - Screening and treatment of microalbuminuria (ACE - Screening and treatment of microalbuminuria (ACE inhibitors , ARBs)inhibitors , ARBs)

To reduce the risk and/or slow the progression of nephropathy To reduce the risk and/or slow the progression of nephropathy

ObjectiveObjective

•Evaluate the effect of ACE inhibitors on the Evaluate the effect of ACE inhibitors on the progression of nephropthy in type 1 diabetic patients.progression of nephropthy in type 1 diabetic patients.

• UAER (Urinary albumin excretion rate) was determined on a sample of 24 hours collected urines using immunoturbidimetric method.

Cytobacteriological exam of urines

Diagnosis of : Persistent microalbuminuria : if at least 2 of 3 analyses in a 6- month period were in the 30 – 299 mg range. Macroalbuminuria ≥ 300 mg /24h • Arterial blood pressure was measured at every visit Hypertension : BP ≥ 140 / 90 mmHg or antihypertensive treatment

• Yearly screening and diagnosis of other degenerative complications (Ocular fundus …).

• Renal function was evaluated after a follow up period of 2 years.

ResultsResults

ParametersParameters MeansMeansMean age (years)Mean age (years) 33.1 33.1 ± 10.7± 10.7Sex ratio (M/W) Sex ratio (M/W) 13 / 2013 / 20Body mass index (kg/mBody mass index (kg/m²)²) 24.24 24.24 ± 4.2± 4.2Duration of diabetes (years)Duration of diabetes (years) 17.6 17.6 ± 5.4± 5.4Mean duration of diabetes at onset Mean duration of diabetes at onset of nephropathy (years)of nephropathy (years) 13.4 ± 5.913.4 ± 5.9Blood pressure SBP (mmHg)Blood pressure SBP (mmHg) 120.7 ± 1.31120.7 ± 1.31 DBP (mmHg)DBP (mmHg) 73.1 73.1 ± 9.1± 9.1Glycated Hemoglobin (%)Glycated Hemoglobin (%) 9.46 9.46 ± 1.97± 1.97Serum Serum creatinincreatinin ( (µmol/l)µmol/l) 69.26 69.26 ± 15.5± 15.5Serum total cholesterol (mmol/l)Serum total cholesterol (mmol/l) 4.67 4.67 ± 1.07± 1.07Serum total triglycerides (mmol/l)Serum total triglycerides (mmol/l) 1.12 1.12 ± 0.69± 0.69Creatinin clearance (ml/mn)Creatinin clearance (ml/mn) 122.4 122.4 ± 44± 44

Baseline Baseline characteristicscharacteristics of patients of patients

Degenerative complications of diabetes : Degenerative complications of diabetes : 81%81%

complicationscomplications Frequency %Frequency %RetinopathyRetinopathyNeuropathyNeuropathy

HypertensionHypertensionLower limb arterial Lower limb arterial

diseasedisease

54.554.557.657.632.432.415.215.2

Evolution of nephropathy in patients Evolution of nephropathy in patients treated by ACE-Inihibitorstreated by ACE-Inihibitors

variablesvariables t0t0 After 1 yearAfter 1 year After 2 yearsAfter 2 years

Glycated hemoglobin (%)Glycated hemoglobin (%) 9.4 ± 2.59.4 ± 2.5 9.2 9.2 ± 2.1± 2.1 8.9 8.9 ± 3,2± 3,2

Microalbuminuria (mg/24H) 111.5111.5± 55.3± 55.3 71.571.5 ± 60.1± 60.1 71.571.5 ± 64.9*± 64.9*

Proteinuria (g/24H) 1.48 1.48 ± 0.73± 0.73 1.49 1.49 ± 0.93± 0.93 1.50 1.50 ± 1.33± 1.33

Serum creatinin (Serum creatinin (µmol/l)µmol/l) 66.2 66.2 ± 13.02± 13.02 82.8 82.8 ± 31.3± 31.3 84.2 84.2 ± 59.1± 59.1

Creatinin clearance (ml/mn)Creatinin clearance (ml/mn) 131.5 131.5 ± 19.4± 19.4 112.1 112.1 ± 24.9± 24.9 109.1 109.1 ± 38.4± 38.4

Systolic blood pressure (Systolic blood pressure (mmHg)mmHg)

Diastolic blood pressure (Diastolic blood pressure (mmHg)mmHg)

120.2 120.2 ± 14.5± 14.5

76.776.7 ± 10.4± 10.4120.2 120.2 ± 17.5± 17.5

74.674.6 ± 11.8± 11.8130.3 130.3 ±24.9±24.9

83.383.3 ± 9.3± 9.3

Serum total cholesterol (mmol/l)Serum total cholesterol (mmol/l) 5.0 5.0 ± 1.0± 1.0 4.4 4.4 ± 0.9± 0.9 4.3 ± 1.14.3 ± 1.1

Serum total triglycerides Serum total triglycerides (mmol/l(mmol/l

1.3 1.3 ± 0.5± 0.5 1.2 1.2 ± 0.4± 0.4 0.9 0.9 ± 0.4± 0.4

* P = 0.05

Evolution of nephropathy in patients Evolution of nephropathy in patients untreated untreated by by ACE-InihibitorsACE-Inihibitors

variablesvariables t0t0 t1t1 t2t2

Glycated hemoglobin (%)Glycated hemoglobin (%) 9.5 9.5 ± ± 1.91.9 8.7 8.7 ± 0.9± 0.9 8,9 8,9 ± 2,1± 2,1

microalbuminuria (mg/24H) 84.0 84.0 ±± 60.3 60.3 91.5 91.5 ± 61.4± 61.4 99.0 99.0 ± 41.1± 41.1

Proteinuria (g/24H) 0.9 0.9 ± 0.± 0. 2.272.27± 0.93± 0.93 2.3 2.3 ± 1.53± 1.53****

Systolic blood pressure (mmHg)Systolic blood pressure (mmHg)Diastolic blood pressure (mmHg)Diastolic blood pressure (mmHg)

113.0 113.0 ± 12.0 ± 12.0 7.3 7.3 ± 0.9± 0.9

118.0 118.0 ±1.1±1.17474 ± 11.1± 11.1

136.6 136.6 ± ± 8.33 8.33 83.3 83.3 ± 2.5± 2.5

Serum creatinin (Serum creatinin (µmol/l)µmol/l) 64.2 64.2 ± 14.13± 14.13 75.0 75.0 ± 17.2± 17.2 63.2563.25 ±± 18.2 18.2Creatinin clearance (ml/mn)Creatinin clearance (ml/mn) 140.7 140.7 ± 42.9± 42.9 115.9 115.9 ± 29.8± 29.8 104.5 104.5 ± 18.7± 18.7**

Serum total cholesterol (mmol/l)Serum total cholesterol (mmol/l) 4.9 4.9 ± 0.9± 0.9 4.6 4.6 ± 1.43± 1.43 6.43 6.43 ± 2.3± 2.3Serum total triglycerides Serum total triglycerides (mmol/l)(mmol/l)

1.3 1.3 ± 0.7± 0.7 1.0 1.0 ±0.53±0.53 1.2 1.2 ± 0.56± 0.56

* p < 0.05 ** P < 0.01

Normoalbumin33%

Amélioration36%

Aggravation26%

Macroalbumi5% renal failure

0%

Evolution of nephropathyEvolution of nephropathy

Diabetics treated by ACE

Diabetics untreated by ACE

renal failure15%

Macroalbumi24%

Aggravation45%

Amélioration21%

Normoalbumin0,0%

Evolution of Evolution of nephropathynephropathy69

2126 24

ACE -

5

55

0

10

20

30

40

50

60

70Pourcentage

Regression Stabilisation Aggravation Evolution of nephropathy

ACE +

ACE -

P = 0.05 p < 0.05

Discussion (1)Discussion (1)• Several studies have shown that ACE Several studies have shown that ACE inhibition is effective in reducing renal inhibition is effective in reducing renal progression in both type 1 and type 2 progression in both type 1 and type 2 diabetic patients with microalbuminuria.diabetic patients with microalbuminuria.

• Effect of ACE inhibition did not differ by Effect of ACE inhibition did not differ by sex, age, disease duration, glycemic control sex, age, disease duration, glycemic control and baseline blood pressure, indicating and baseline blood pressure, indicating benefit for all patients regardless of these benefit for all patients regardless of these variables.variables.

A meta-analysis (ATLANTIS, ESPRIT, PRIMA, A meta-analysis (ATLANTIS, ESPRIT, PRIMA, EUCLID…) showed that in normotensive EUCLID…) showed that in normotensive patients with type 1 diabetes and patients with type 1 diabetes and microalbuminuria, ACE inhibitors :microalbuminuria, ACE inhibitors :- reduced siginificantly progression from - reduced siginificantly progression from microalbuminuria to macroalbuminuria by microalbuminuria to macroalbuminuria by 79%.79%.- at 2 years, albumin excretion rate (AER) was - at 2 years, albumin excretion rate (AER) was 50.5 % lower in treated patients than in 50.5 % lower in treated patients than in placebo group. placebo group. - Adjustment for change in blood pressure - Adjustment for change in blood pressure attenuated the treatment difference to 45.1 %.attenuated the treatment difference to 45.1 %.

Ann Int Med 2001, 134:370-379Ann Int Med 2001, 134:370-379

Discussion (2)Discussion (2)

ConclusionConclusion• Annual screening for microalbuminuria to start Annual screening for microalbuminuria to start

specific treatment as soon as possible. specific treatment as soon as possible. - Optimal blood glucose and blood pressure controls- Optimal blood glucose and blood pressure controls - Blockage of the renin-angiotensin system with ACE - Blockage of the renin-angiotensin system with ACE (type 1 diabetes) and ARBs (type 2 diabetes)(type 1 diabetes) and ARBs (type 2 diabetes) major therapeutic strategies to improve renal major therapeutic strategies to improve renal

prognosis, reduce cardiovascular events and prognosis, reduce cardiovascular events and preserve life quality of diabetics.preserve life quality of diabetics.

Thank you for your attention