# Abstract

 

## Background Increased prevalence of metabolic syndrome (MS) is observed in psoriasis. Metformin has shown improvement in cardiovascular risk factors while pioglitazone demonstrated anti proliferative, anti-inflammatory and anti angiogenic effects. Study objective is to evaluate the efficacy and safety of Insulin sensitizers (metformin and pioglitazone) in psoriasis patients with metabolic syndrome (MS). 

## Methods Single centre, parallel group, randomized, study of metformin, pioglitazone and placebo in psoriasis patients with MS. 

## Results Statistically significant improvement was observed in Psoriasis Area and Severity Index (PASI), Erythema, Scaling and Induration (ESI) and Physician global assessment (PGA) scores in pioglitazone (*p* values -- PASI = 0.001, ESI = 0.002, PGA = 0.008) and metformin groups (*p* values -- PASI = 0.001, ESI = 0.016, PGA = 0.012) as compared to placebo. There was statistically significant difference in percentage of patients achieving 75 % reduction in PASI and ESI scores in metformin (*p* value -- PASI = 0.001, ESI = 0.001) and pioglitazone groups (*p* vaue -- PASI = 0.001, ESI = 0.001). Significant improvement was observed in fasting plasma glucose (FPG) and triglycerides levels in metformin and pioglitazone arms. Significant improvement was noted in weight, BMI, waist circumference, FPG, triglycerides and total cholesterol after 12 weeks of treatment with metformin while pioglitazone showed improvement in FPG, triglyceride levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and LDL cholesterol levels. There was no difference in pattern of adverse drug reaction in three groups. 

## Conclusion Insulin sensitizers have shown improvement in the parameters of MS as well as disease severity in psoriasis patients. 

## Trial registration CTRI Registration Number: [ CTRI/2011/12/002252](#). Registered on 19/12/2011. # Results A total of 83 consecutive adult psoriasis patients with MS were screened from June 2010 to April 2011 (Fig. [1](#)). Out of 83 patients, 23 were excluded from the study. 23, 16 and 21 patients were randomized to placebo, pioglitazone and metformin treatment groups respectively. Disposition of patients and reasons for withdrawal were summarized in Fig. [1](#). Hence, 21 patients in placebo arm, 16 in pioglitazone and 18 patients in metformin arm completed the study. As Intention to treat analysis with last observation carry forward (LOCF) was done, so all the subjects as randomized were included for final analysis. <figure> <p><img src="" /></p> <figcaption>Flowchart of the patients enrolled in the study depicting enrollment, withdrawal and follow up of the subjects</figcaption> </figure> No significant difference was observed in baseline demographics and MS characteristics among three treatment groups except past history of remission (Table [1](#)). ::::table-wrap

::: caption
Baseline characteristics of three treatment groups
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Baseline characteristics Placebo (*n* = 23) Metformin (*n* = 21) Pioglitazone (*n* = 16) *p*-value

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Age (years) Mean (±SD) 46.9 (±10.4) 45.1 (±13.0) 44.0 (±12.9) 0.747
Male/Females, *n* (%) 14/9 (60.9/39.1) 12/9 (57.1/42.9) 9/7 (56.3/43.7) 0.950
Total duration of disease (years) Mean (±SD) 9.1 (±8.6) 6.0 (±6.9) 6.9 (±11.2) 0.492
Seasonal Exacerbation, *n* (%) 13 (56.5) 13 (61.9) 6 (37.5) 0.313
Seasonal improvement, *n* (%) 13 (56.5) 13 (61.9) 5 (31.3) 0.152
Remission, *n* (%) 21 (91.3) 11 (52.4) 10 (62.5) 0.014
Nail involvement, *n* (%) 17 (73.9) 13 (61.9) 12 (75.0) 0.602
Joint involvement, *n* (%) 7 (30.4) 5 (23.8) 4 (25.0) 0.870
DM, *n* (%) 2 (8.7) 3 (14.3) 3 (18.6) 0.653
HTN, *n* (%) 11 (47.8) 10 (47.6) 5 (31.3) 0.523
Family H/O Psoriasis, *n* (%) 4 (17.4) 3 (14.3) 0 (0) 0.225
Alcohol, *n* (%) 6 (26.1) 8 (38.1) 6 (37.5) 0.643
Smoking, *n* (%) 3 (13.0) 3 (14.3) 1 (6.3) 0.727
Vegetarian, *n* (%) 10 (43.8) 11 (52.4) 12 (75.0) 0.144
BMI (kg/m^2^), Mean (±SD) 29.5 (±3.7) 27.6 (±3.7) 27.4 (±4.3) 0.151
Waist Circumference (cm), Mean (±SD) 105.3 (±9.1) 99.0 (±9.9) 100.2 (±8.7) 0.70
ESI, Mean (±SD) 5.9 (±1.6) 5.3 (±1.5) 5.4 (±1.3) 0.412
PGA, Mean (±SD) 3.4 (±0.9) 3.1 (±0.8) 3.2 (±0.8) 0.476
FPG (mg/dl), Mean (±SD) 97.6 (±20.8) 101.9 (±35.1) 103.4 (±28.9) 0.797
Total Cholesterol (mg/dl), Mean (±SD) 184.4 (±37.5) 206.9 (±36.2) 207.2 (±42.3) 0.95
Triglycerides (mg/dl), Mean (±SD) 181.8 (±61.3) 194.3 (±63.1) 200.1 (±55.9) 0.623
HDL (mg/dl), Mean (±SD) 45.1 (±13.5) 44.3 (±6.6) 45.0 (±9.7) 0.968
LDL (mg/dl), Mean (±SD) 107.6 (±35.7) 126.1 (±29.1) 123.1 (±42.3) 0.194
SBP (mmHg), Mean (±SD) 130.4 (±11.5) 130.6 (±12.9) 135.6 (±11.5) 0.344
DBP (mmHg), Mean (±SD) 84.7 (±7.9) 85.9 (±7.9) 85.6 (±8.5) 0.875
Calcium channel blockers, *n* (%) 5 (21.7) 3 (14.3) 3 (18.6) 0.815
Beta blockers, *n* (%) 2 (8.7) 1 (4.8) 0 (0) 0.471
Angiotensin receptor blockers, *n* (%) 2 (8.7) 2 (9.5) 0 (0) 0.456
ACE inhibitors, *n* (%) 1 (4.3) 0 (0) 1 (6.3) 0.543
Diuretics, *n* (%) 0 (0) 0 (0) 1 (6.3) 0.247
Sulfonylureas, *n* (%) 2 (8.7) 0 (0) 1 (6.3) 0.403
Anxiolytics, *n* (%) 1 (4.3) 1 (4.8) 0 (0) 0.684
Lithium, *n* (%) 1 (4.3) 0 (0) 0 (0) 0.441
Antidepressants, *n* (%) 1 (4.3) 2 (9.5) 0 (0) 0.413
Insulin, *n* (%) 0 (0) 1 (4.8) 0 (0) 0.389
Modafinil, *n* (%) 0 (0) 1 (4.8) 0 (0) 0.389
NSAIDS, *n* (%) 0 (0) 1 (4.8) 0 (0) 0.389
Ca, Vitamin D, *n* (%) 0 (0) 1 (4.8) 0 (0) 0.389
Steroids, *n* (%) 0 (0) 0 (0) 1 (6.3) 0.247
Beta 2 agonists, *n* (%) 0 (0) 0 (0) 1 (6.3) 0.247

*DM* diabetes mellitus, *HTN* hypertension, *BMI* body mass index, *ESI*
erythema, scaling and Induration, *PFA* physician global assessment,
*FPG* fasting plasma glucose, *HDL* high density lipoprotein, *LDL* low
density lipoprotein, *SBP* systolic blood pressure, *DBP* diastolic
blood pressure, *ACE inhibitors* angiotensin converting enzyme
inhibitors

Values are presented as Mean (±SD) or *n* (%):::: 

## ESI and PGA scores and parameters of Metabolic Syndrome (MS) Statistically significant improvement was observed in PASI, ESI and PGA scores in pioglitazone (*P* values -- PASI = 0.001, ESI = 0.002, PGA = 0.008) and metformin groups ( *P* values -- PASI = 0.001, ESI = 0.016, PGA = 0.012) as compared to placebo (Fig. [2](#)). There was statistically significant difference in percentage of parameters of MS improved following 12 weeks of treatment in pioglitazone (15 %) and metformin (16.2 %) groups as compared to placebo (3.5 %) (Fig. [3](#)). Statistically significant difference in percentage of patients achieving 75 % reduction in PASI and ESI scores in metformin (*p* value -- PASI = 0.001, ESI = 0.001) and pioglitazone groups (*p* value -- PASI = 0.001, ESI = 0.001) (Fig. [4](#)). Statistically significant improvement is observed in FPG, total cholesterol and triglycerides levels (Table [2](#)) in metformin and pioglitazone arms as compared to placebo. Significant improvement was also observed in percentage of patients achieving 75 % reduction in PGA scores (Fig. [4](#)) and change in weight and waist circumference in metformin group as compared to placebo (Table [2](#)). Significant improvement was observed in weight, BMI, waist circumference, FPG, triglycerides and total cholesterol after treatment with metformin (Table [2](#)). Similarly improvement was seen in FPG, triglyceride levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and LDL cholesterol levels after treatment with pioglitazone for 12 weeks (Table [2](#)). No significant change in the IL-6 and TNF-α levels among three groups (Fig. [5](#)). <figure> <p><img src="" /></p> <figcaption>Mean change in PASI, ESI and PGA scores in three treatment groups from baseline (Intention to treat Analysis). || = Inter-group comparisons for PASI, ESI and PGA scores at 12 weeks as compared to baseline was carried out by One Way ANOVA, post hoc test used Scheffe; † = metformin vs placebo, ‡ = Pioglitazone vs placebo,\*\* = metformin vs pioglitazone. PASI - Psoriasis area and severity index, ESI – Erythema, Scaling and Induration, PGA – Physician Global Assessmenty</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Percentage of parameters of metabolic syndrome (MS) improved following 12 weeks of treatment in placebo, metformin and pioglitazone groups from baseline (Intention to treat Analysis). Inter-group comparisons for percentage of parameters of metabolic syndrome improved carried out by Chi-square test. * = Placebo vs metformin, † = placebo vs pioglitazone, ‡ = metformin vs pioglitazone; MS = Metabolic syndrome</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Percentage of patients achieving 75 % reduction in PASI, ESI and PGA scores in placebo, metformin and pioglitazone groups from baseline (Intention to treat Analysis). Inter-group comparisons for 75 % reduction in PASI, ESI and PGA scores between three treatment groups carried out by Chi-square test. * = placebo vs metformin, † = metformin vs pioglitazone, ‡ = placebo vs pioglitazone. PASI - Psoriasis area and severity index, ESI – Erythema, Scaling and Induration, PGA – Physician Global Assessment</figcaption> </figure> ::::table-wrap
::: caption
Mean Change in individual parameters of metabolic syndrome after
12 weeks of treatment in three treatment groups from baseline (Intention
to treat Analysis)
:::

Treatment Placebo (*n*  = 23) Metformin (*n*  = 21) Pioglitazone (*n*  = 16) ANOVA with post hoc Tukey's ^b^

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Parameters Mean change [Mean ± SD] *p* value^a^ Mean change [Mean ± SD] *p* value^a^ Mean change [Mean ± SD] *p* value^a^ Between groups, df = 2, *p* value
Weight (kg) −0.6 ± 3.1 0.338 1.1 ± 1.9 0.016^f^ −0.4 ± 1.7 0.324 0.048^c^, 0.970^d^, 0.129^e^
BMI (kg/m^2^) −0.1 ± 1.4 0.663 0.4 ± 0.7 0.016^f^ −0.2 ± 0.7 0.370 0.186^c^, 0.995^d^, 0.210^e^
Waist circumference (cm) −0.9 ± 4.0 0.314 1.9 ± 2.7 0.003^f^ 0.9 ± 2.3 0.119 0.013^c^, 0.200^d^, 0.606^e^
FPG (mg/dl) 2.2 ± 10.0 0.312 15.2 ± 19.2 0.002^f^ 20.5 ± 17.4 \<0.001^f^ 0.021^c^, 0.002^d^,0.577^e^
Triglycerides (mg/dl) 1.1 ± 43.3 0.903 44.3 ± 45.4 \<0.001^f^ 53.3 ± 36.9 \<0.001^f^ 0.004^c^, 0.001^d^, 0.798^e^
HDL (mg/dl) −1.7 ± 6.6 0.221 −1.9 ± 4.6 0.060 −1.5 ± 9.6 0.544 0.992^c^, 0.994^d^, 0.974^e^
SBP (mm Hg) 0.0 ± 8.6 1.000 1.7 ± 6.7 0.257 5.1 ± 6.3 0.005^f^ 0.725^c^, 0.094^d^, 0.354^e^
DBP (mm Hg) 0.3 ± 7.9 0.876 1.7 ± 4.2 0.077 4.1 ± 5.5 0.009^f^ 0.546^c^, 0.085^d^, 0.475^e^
Total Cholesterol (mg/dl) 1.4 ± 29.2 0.816 21.8 ± 25.2 0.001^f^ 24.0 ± 29.5 0.005^f^ 0.049^c^, 0.042^d^, 0.970^e^
LDL (mg/dl) −5.9 ± 28.3 0.324 6.6 ± 20.0 0.146 9.8 ± 11.6 0.004^f^ 0.151^c^, 0.079^d^, 0.898^e^

*FPG* fasting plasma glucose, *HDL* high density lipoprotein, *SBP*
systolic blood pressure, *DBP* diastolic blood pressure, *BMI* body mass
index, *LDL* low density lipoprotein

^a^ Intra-group comparisons for weight, BMI, individual parameters of
lipid profile and metabolic syndrome carried out by Paired *T*-test

^b^ Inter-group comparisons for individual parameters carried out by One
way ANOVA, post hoc Tukey's test

^c^ Metformin vs placebo

^d^ pioglitazone vs placebo

^e^ metformin vs pioglitazone

^f^ statistically significant difference compared to baseline:::: <figure> <p><img src="" /></p> <figcaption>Mean decrease in levels of IL-6 and TNF-α in three treatment groups from baseline in subgroup of patients (Intention to treat Analysis). Values are expressed as Mean ± SD. Inter-group comparisons for IL-6 and TNF-α carried out by One way ANOVA, \*- Metformin vs placebo, †- pioglitazone vs placebo, ‡ - metformin vs pioglitazone, IL-6 – Interleukin-6, TNF-α – Tumor necrosis factor-α</figcaption> </figure> No significant difference in the mean number of adverse events in three groups except for weight gain between metformin and pioglitazone (Table [3](#)). ::::table-wrap
::: caption
Adverse events observed during the study in placebo, metformin and
pioglitazone treatment groups in topical treatment arm
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Adverse Event Placebo (*N* = 23) Metformin (*N* = 21) Pioglitazone (*N* = 16) *P* value (Fischer's Exact test)

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Redness 1 1 0 >0.99^a^, >0.99^b^ ,>0.99 ^c^
Pain 1 0 0 >0.99^a^, >0.99^b^ ,>0.99 ^c^
Hyperpigmentation 7 5 4 0.74^a^, >0.99^b^  > 0.99^c^
Hypopigmentation 0 1 1 0.477^a^, 0.41^b^  > 0.99 ^c^
Exacerbation 2 3 0 0.658^a^, 0.503^b^, 0.243^c^
Hypothyroidism 1 0 0 >0.99^a^, >0.99^b^
Edema 0 0 2 0.162^b^, 0.180^c^
c/o Weight Gain 0 0 2 0.162^b^, 0.180^c^
Anemia 0 0 0 -
Abdominal Pain 0 1 0 0.477^a^, >0.99^c^
Headache 0 0 0 -
Gastritis 0 0 0 -
Nausea 0 0 0 -
Vomiting 0 0 0 -
Dizziness 0 0 0 -
Diarrhea 0 1 0 0.477^a^, >0.99^c^
Heartburn 0 1 0 0.477^a^, >0.99^c^

> 3 times SGOT/SGPT 0 0 0 -
> Slight increase in SGOT/SGPT 0 0 0 -
> Increased TLC 0 0 0 -
> Weight gain > 1 kg 8 3 8 0.169^a^, 0.509^b^, 0.030^c^
> Recurrence after 3 months 4 6 5 0.377^a^, 0.312^b^, 0.860^c^

Inter group comparison between groups was done by Fischer's Exact test;
*p* -- value ≤ 0.05 was considered statistically significant

^a^ placebo vs metformin

^b^ placebo vs pioglitazone

^c^ metformin vs pioglitazone::::


Extracted trial result:
Outcome: IL-6 and TNF-α levels (continuous)
Intervention: metformin or pioglitazone
Comparator: placebo
Intervention group size: 37
Comparator group size: 23
Notes: Values combined and given in figure