Actos and Metformin in women with Polycystic Ovary

Syndrome not optimally responsive to Metformin

Glueck CJ, Goldenberg NM, Wang P, Sieve L

ACTOS

• Used for the treatment of type 2 DM

• Insulin sensitizing agent (PPAR- γ receptor)

• Class C agent during pregnancy

OBJECTIVE:

• Assess efficacy-safety of Actos (45 mg/d, median 10 months) when added to antecedent metformin (2.55 g/d, median 12 months) and diet, in 15 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin and diet

DESIGN:

• Prospective open label study of treatment of PCOS with metformin-diet, Actos-metformin-diet

• Metformin-diet: 15 non-responsive vs 30 responsive women with PCOS for 12 months

• Actos-metformin-diet: 13 of the non-responsive women for 10 months compared to their antecedent 12 months on metformin+diet

• Setting: Outpatient clinical research center

PATIENTS:

• 15 oligo-amenorrheic women with PCOS not optimally responsive to metformin+diet (did not resume normal menses, did not lose weight, did not reduce hyperandrogenemia)

• 30 oligo-amenorrheic women with PCOS, matched by age and previous menstrual history, responsive to metformin+diet

INTERVENTIONS:• Diet (1500 calorie, 26% protein, 44%

carbohydrate [42% complex], 40% fat, polyunsaturated/saturate ratio 2/1) throughout

• Metformin (2.55 g/day) given to two cohorts of women (n =15 non-responsive, n = 30 responsive) for medians of 12, 13 months

• Actos (45 mg/d) added for median 10 months in 13 of the non-responsive women

Main Outcome Measures:

• Menstrual status

• Changes in sex hormones

• Insulin• Insulin resistance (IR), insulin secretion

by HOMA model

• Cholesterol

Actos-Metformin Results:

• In the 13 non-responsive women who took metformin + Actos for a median of 10 months, compared to metformin-diet alone:

• On Actos + metformin:

• DHEAS fell (200 to 160 ug/dl, p =. 0046), • Insulin fell (16 to 11 uU/ml, p =. 0007), IR fell (3.73 to

2.11, p =. 003), insulin secretion fell (221 to 125, p=.0005),

• HDL cholesterol rose (38 to 41 mg/dl, p=.033)

13 non-Responders on Met for 12 months vs on Met+ Actos for 10 months

251241 242

200

210

220

230

240

250

260

Weight

251221

125

50

150

250

HOMA B-cell Fx

Baseline on Met on Met+ Actos

2316.2

11

0

5

10

15

20

25

Insulin (uU/ml)

4.243.73

2.11

0

2

4

6

HOMA IR

Baseline on Met on Met+ Actos

184 200160

100

120

140

160

180

200

DHEAS(ug)/dl)

P=.15 P=.34P=.24

P=.0005

P=.47P=.0046

P=.15

P=.0034P=.033

P=.0007

Results: Menstrual Status

• Non-responders: Versus 14% at pre-treatment baseline, at 3, 6, 9, and 12 months on metformin, 46% (p=.042), 38% (p=.03), 27%, and 24% of expected menses occurred

• Responders: Versus 12% at pre-treatment baseline, at 3, 6, 9, and 12 months on metformin, 75%, 81%, 88%, and 94% of expected menses occurred, p =. 036, =. 0009, .0007, <. 0001 compared to 15 non-responsive women

Menstrual Status on Actos-metformin

By paired comparison with metformin alone, 67% vs 46% of expected menses occurred at 3 months (p = .09), 77% vs 38% at 6 months (p = .004), 73% vs 27% at 9 months (p= .016)

Percent of menses occurring in women with PCOS

Comparison of 2 groups on Met

0

20

40

60

80

100

0 3 months 6 months 9 months 12months

% of

expe

cted m

ense

s

Responders Non-responders

Non-responders after Actos was added

0 months 3months 6 months 9 months

Non-responders

P=.094

.0039 .016

Responders better over 12 months p=0.0002 Non-responders

improved over

9 months P=.016

SAFETY (Actos-Metformin): No change in liver function

tests. No edema. No hypoglycemia

CONCLUSION:

• In women with PCOS who failed to respond optimally to metformin, when Actos was added, insulin, insulin resistance, insulin secretion, and DHEAS fell, HDL cholesterol rose, and menstrual regularity improved, without adverse side effects