Clinical studies of renin angiotensin aldosterone system inhibition and outcomes of insulin resistance

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ACE inhibition with captopril improves insulin sensitivity [107], in some cases allowing withdrawal of sulfonylurea and reduction of the insulin dose [108,109]. Hence, a few randomized trials have attempted to assess changes in insulin sensitivity comparing ACE inhibitor and placebo (Table 8) [110-117]. The results were heterogeneous, but the use of ARBs to assess insulin sensitivity seemed to show some promise, and these results were not quite as heterogeneous as those seen with ACE inhibitors. Of the seven studies shown in Table 9, five showed success in

Table 7

Prevention of type 2 diabetes mellitus by renal angiotensin aldosterone inhibition

Table 7

Prevention of type 2 diabetes mellitus by renal angiotensin aldosterone inhibition

Treatment arm:

Control arm:

P Value

number of

Treatment arm:

total number

Control arm:

favoring

patients with

total number

of patients with

total number

Relative

Confidence

treatment

Study

type 2 diabetes

of subjects

diabetes mellitus

of patients

risk

interval

arm

CAPP (1999)

227

5184

280

5229

0.89

0.70-1.03

NS

STOP-HTN-2

99

1969

97

1961

0.95

0.72-1.26

NS

(1999)

LIFE (2002)

241

4006

319

3592

0.75

0.63-0.88

P = 0.001

HOPE (2001)

102

2837

155

2883

0.66

0.51-0.85

P < 0.001

ALLHAT

119

5840

302

9733

0.66

0.53-0.81

P < 0.001

(2002)

SOLVD (2003)

9

153

31

138

0.26

0.13-0.53

P < 0.001

ALPINE (2003)

1

196

8

196

0.13

0.02-0.97

P = 0.03

SCOPE (2003)

99

2160

125

2170

0.81

0.62-0.06

NS

CHARM (2003)

163

2715

202

2721

0.81

0.66-0.97

P < 0.001

VALUE (2004)

690

7649

845

7596

0.77

0.69-0.86

P < 0.0001

Definitions: ALPINE, Antihypertensive treatment and Lipid Profile in a North of Sweden Efficacy; SCOPE, Study of Cognition and Prognosis in the Elderly.

Table 8

Main randomized, placebo-controlled trials examining the effect of long-term administration of angiotensin-converting enzyme inhibitors

on insulin sensitivity in patients

with hypertension and/

or type 2 diabetes

or impaired glucose tolerance

Change in

Insulin

insulin

ACE Inhibitor,

Patient

Duration of

No. of

Main

Run-in/

sensitivity

sensitivity

Reference

dosage

characteristics

treatment

patients

Blinding

comparator

washout

assessment

versus placebo

Paolisso

lisinopril

elderly

2 wks

18

double

placebo

2 wks/1 wk

IVGTT

18% increase

et al, 1992

20 mg/d

hypertensives

Bak et al,

perindopril

hypertensives

6 wks

10

double

placebo

2 wks/no

IVITT

no change

1992

4 mg/d

and type 2 diabetics

washout

Santoro

cliazapril

hypertensives

12 wks

20

open

placebo

8 wks/NA

clamp

no change

et al, 1993

5 mg/d

Paolisso

lisinopril

elderly

8 wks

30

single

placebo

3 wks/3 wks

clamp

33% increase

et al, 1995

20 mg/d

hypertensives

Thurig et al,

lisinopril

hypertensives

8 wks

24

double

placebo

8 wks/no

IVGTT

no change

1995

20 mg/d

washout

Vuorinen-Markkola

enalapril

hypertensives

4 wks

4

double

placebo

4 wks/NA

clamp

30% increase

and Yki-Jarvinen,

20-40 mg/d

and type

1995

2 diabetics

Ferri et al,

captopril

type 2

1 wk

15

double

placebo

none/NA

clamp

14% increase

1995

25 mg bid

diabetics

Falkner et al,

lisinopril

black hypertensives

12 wks

16

single

placebo

8 wks/NA

clamp

16% increase

1995

10-40 mg/d

Bohlen et al,

perindopril

overweight

6 wks

20

double

placebo

4 wks/NA

IVGTT

no change

1996

4 mg/d

hypertensives

De Mattia

captopril

type 2 diabetics

10 days

14

double

placebo

no washout

clamp

41% increase

et al, 1996

50 mg/d

Wiggam et al,

captopril

hypertensives

8 wks

18

double

placebo

6 wks/6 wks

clamp

no change

1998

50 mg bid

Petrie et al,

trandolapril

hypertensives and

4 wks

16

double

placebo

2 wks/2 wks

clamp

no change

2000

2 mg/d

type 2 diabetics or persons with impaired glucose tolerance

Definitions: IVGTT, intravenous glucose tolerance test; IVITT, intravenous insulin tolerance test; NA, not applicable.

Definitions: IVGTT, intravenous glucose tolerance test; IVITT, intravenous insulin tolerance test; NA, not applicable.

Table 9

Main trials examining the effect of long-term therapy with angiotensin II type 1 receptor antagonists on insulin sensitivity in patients with hypertension and/or insulin resistance and/or impaired glucose tolerance

Table 9

Main trials examining the effect of long-term therapy with angiotensin II type 1 receptor antagonists on insulin sensitivity in patients with hypertension and/or insulin resistance and/or impaired glucose tolerance

ATj-receptor

Insulin

Change in

antagonist,

Patient

Duration of

No. of

Main

Run-in/

sensitivity

insulin

References

dosage

characteristics

treatment

patients

Blinding

comparator

washout

assessment

sensitivity

Moan et al,

losartan 50 mg/d

hypertensive

3-12 wks

5

NA

NA

3 d washout

clamp

30% increase

1995

first 2 weeks, then 100 mg/d

Laakso et al,

losartan 50 mg/d

hyperinsulinaemic

12 wks

20

double

metoprolol

4-6 wks

clamp

no change

1996

and hypertensive

95 mg/d

washout

Paolisso et al,

losartan 50 mg/d

insulin resistant

4 wks

16

single

placebo

1 wk run-in

clamp

increase of NOGM

1997

and hypertensive

Fogarl et al,

losartan 50 mg/d

overweight

6 wks/6 wks

28

double,

perindopril

6 wks washout

clamp

ACE I improves

1998

crossover

4 mg/d

insulin resistance

Fogarl et al,

losartan 50 mg/d

hypertensive

6 wks

25

double,

lisinopril

4 wks washout

clamp

ACE I improves

1998

crossover

20 mg/d

insulin resistance

Trendwalker

candesartan cliexetil

hypertensive and

12 wks

161

double

placebo

4 wks run-in

serum HbA1c,

no change

et al, 1998

8-16 mg/d

type 2 diabetics

glycemia and lipid profile

Higashiura

candesartan

hypertensive

2 wks

8

NA

NA

2 wks run-in

clamp

increase

et al, 1999

Definitions: HbA1c, predominant glycosylated hemoglobin; NA, not applicable; NOGM, nonoxidative metabolism.

Definitions: HbA1c, predominant glycosylated hemoglobin; NA, not applicable; NOGM, nonoxidative metabolism.

improving insulin sensitivity [118-124]. Several factors make the results of these trials using ACE inhibitors or ARBs less robust overall. Different choice of experimental models, target molecules, doses, and route of administration may all have contributed to the conflicting results. In addition, the measure of insulin resistance itself is fraught with problems because of its sensitivity, specificity, positive and negative predictive values, reproducibility, discrimination, and calibration. The parameters used in evaluating glucose homeostasis are not always equivalent or comparable. Clearly, there is a need to improve the modeling technique by using refined methods of quantifying insulin resistance to predict more accurately the likelihood of developing diabetes and cardiovascular disease [125]. At present, metabolic syndrome variables may well be the best predictors for evaluating the likelihood of coronary artery disease.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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