Randomized placebo control study of insulin sensitizers (Metformin and Pioglitazone) in psoriasis patients with metabolic syndrome (Topical Treatment Cohort)

Psoriasis is a chronic, inflammatory multisystemic disorder with genetic basis affecting 2-3 % of world population and affecting about 0.4 % of Asians [1]. Psoriasis has been found to be associated more commonly with obesity, metabolic syndrome (MS) [1, 2], diabetes mellitus [3] and increased cardiovascular (CVS) mortality and morbidity [4‐6]. Metabolic syndrome (MS) is a cluster of risk factors including central obesity, atherogenic dyslipidemia, hypertension and glucose intolerance and is a strong predictor of cardiovascular diseases, diabetes and stroke [7‐9]. Many cytokines (e.g. interferon-γ, TNF-α, IL-6, IL-8, IL-12, IL-17, IL-19 and IL-23) involved in the pathogenesis of psoriasis are also known to contribute to the cascade of metabolic syndrome such as hypertension, dyslipidemia and insulin resistance [10]. Prodifferentiating, antiproliferative, anti-inflammatory and antiangiogenic effects of Peroxisome proliferator-activated receptor- γ (PPAR-γ) ligands may potentially have beneficial role in psoriasis [11‐13] as exemplified by demonstrated efficacy of Thiazolidinediones (TZDs) in treatment of psoriasis [14‐18]. Metformin is an ‘insulin sensitiser’, lowers glucose levels without increasing insulin secretion. It has shown additional beneficial effects in adults with type 2 diabetes, including weight reduction, decreasing hyperinsulinemia, improving lipid profiles, augmented fibrinolysis and enhanced endothelial function [19‐21], that all are usual metabilic abnormalities observed in subjects with MS. Therfore we anticipated that such pharmacological effects observed with metformin might be of use in psoriatic patients with MS. To the best of our knowledge no study till date has evaluated metformin and pioglitazone head to head in patients of psoriasis with MS. Present study was planned as comparative evaluation of safety & efficay of metformin with pioglitazone in placebo controlled setting in patients of psoriasis with MS.

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.

No significant difference was observed in baseline demographics and MS characteristics among three treatment groups except past history of remission (Table 1).

Baseline characteristics were similar among three treatment groups except for percentage of individuals having remission. The difference observed in baseline characteristic is unlikely to be of clinical significance and could not have accounted for the higher efficacy observed in metformin and pioglitazone groups in comparison to placebo group. All patients were given topical 5 % coal tar treatment. As the compliance achieved is around 90 %, which is ensured by direct questioning and pill count, it is less likely that topical treatment with 5 % coal tar would have resulted in the differences in efficacy among three treatment groups. In our study, metformin and pioglitazone cause significant improvement in PASI, ESI and PGA scores as compared to placebo.

In metformin, pioglitazone and placebo group, 52.4 %, 50 % and 17.4 % of the patients had complete improvement in MS respectively (metformin vs placebo – OR (95 % CI), 5.2 (1.3–20.7), P value = 0.019; pioglitazone vs placebo – (OR (95 % CI) = 4.8 (1.1–20.4), P value = 0.036; metformin vs pioglitazone – (OR (95 % CI) = 0.9 (0.2–3.3), P value = 0.886). Therefore, metformin and pioglitazone beneficial effect on MS parameters might be accounted for the improved efficacy in psoriasis disease itself.

Clinical studies had also demonstrated the proof of efficacy of TZDs in psoriasis. Pioglitazone had demonstrated superior efficacy to placebo group alone as well as in combination therapy with acitretin in psoriasis patients [14, 15]. Two open label studies [16, 17] had demonstrated marked improvement in psoriasis lesions with troglitazone in chronic plaque type psoriasis patients. Robertshaw and Friedman [18] have also demonstrated excellent improvement with pioglitazone in 4 out of 5 patients with chronic plaque type psoriasis in an open label, pilot study.

Study done by Bongartz et al (2005) with pioglitazone 60 mg/day for 12 weeks in psoriatic arthritis patients with tender and swollen joints, demonstrated 60 % of the patients met the psoriatic arthritis response criterion. Mean percentage reduction in PASI was 38 %, along with median tender joint count decreased from 12–4 and median swollen joint count from 5 to 2 (P <0.05 for both) [25]. The observed higher percentage reduction in ESI and PGA scores in our study is thus expected and is a demonstration of pioglitazone efficacy.

To the best of our knowledge, effect of metformin in psoriasis patients with MS as done in our study has not been explored earlier. Our study has demonstrated improved efficacy of metformin in psoriasis disease itself as well as features of MS. A population based case control study Brauchli et al estimated the decreased risk of developing a first-time psoriasis diagnosis with metformin use as compared to matched controls [OR = 0.77 (95 % CI – 0.62–0.96)] [26]. One case of psoriasiform drug eruption associated with metformin usage has been observed, which on dechallenge and rechallenege leads to improvement and reappearance of lesions respectively [27]. In view of the case report, it has to be kept in mind that there can be clinical worsening of psoriasis with the use of metformin for treatment of psoriasis.

The anti-proliferative [16, 28], pro-differentiating [29], anti-inflammatory [11, 12, 30] and anti-angiogenic [31, 32] effects of TZDs seen in other studies may underlie the observed beneficial anti-psoriatic effects of pioglitazone. Metformin act through activation of adenosine monophosphate-activated protein kinase (AMPK) in extracellular signal-related kinase (ERK1/2) signaling pathway leading to cell cycle arrest and therefore inhibition of cell proliferation, hallmark of psoriasis [33]. AMPK activation not only inhibits iNOS, dendritic, T cell and monocyte/macrophage activation but also activates IL-10 and TGF-β, thereby exerting its anti-inflammatory action [34]. The anti-proliferative and anti-inflammatory action of metformin might have resulted in improvement of psoriasis.

In diabetics, metformin had shown to decrease HbA_1C, total and LDL cholesterol, serum triglycerides, fasting insulin levels and improves HDL cholesterol [35‐37]. Metformin has shown to improve cardiovascular outcomes by mitigating apoptosis [38]. These results are similar to the results observed in our study. In our study, although an increase in mean weight and BMI was observed with pioglitazone but decrease in mean waist circumference was also observed. Clinical studies had shown despite the weight gain reported in all the studies, which may equal as much as 0.5 kg per month for monotherapy, mean waist to hip ratio remains invariably unchanged. In one study, favorable effect on body fat distribution was demonstrated when patients with type II diabetes were treated with pioglitazone 45 mg/day for 16 weeks [39]. MR imaging revealed that pioglitazone decreased visceral fat area and increased subcutaneous fat mass. With 1H-MR spectroscopy in same group of patients, significant decrease in liver fat content was demonstrated. Thus, thiazolidinedione’s (TZDs) have favorable effects on body fat distribution, intra hepatic fat content and adipose tissue metabolism, all resulting in increased insulin sensitivity.

Our study had revealed a mean fall of 20.5 mg/dl in FPG in psoriasis patients with MS with pioglitazone 30 mg/day. PROFIT-J study have shown improvement in glycemic control, DBP and lipid profile [40]. In clinical trials, pioglitazone monotherapy at a dose of 30 mg/day revealed a dose dependent lowering of FPG by 1.0–3.1 mmol/L and HbA_1C reductions ranging between 0.3 and 1.08 % from baseline, significant when compared with placebo [41‐45]. Pioglitazone increases peripheral insulin sensitivity, enhancing both splanchnic and peripheral glucose uptake, in patients with type II diabetes in randomized, placebo controlled, 12–26 weeks trial [40, 46, 47]. We observed a mean decrease in serum triglycerides, total cholesterol and LDL cholesterol of 53.3, 24 and 9.8 mg/dl respectively, with pioglitazone 30 mg/day. Lipid profiles generally improved in pioglitazone recipients in three placebo controlled 12–26 week trial [41, 42, 48]. Favorable increases in HDL cholesterol were greater in pioglitazone than placebo recipients in three trials [40, 42, 48].

Mean reduction in SBP and DBP of 5.1 and 4.1 mmHg respectively was measured in pioglitazone group in our study, which was significant as compared to baseline. In a review article by Giles et al, the observed magnitude of reduction was 4–5 mmHg in SBP and 2–4 mmHg in DBP, which were sufficient to significantly reduce cardiovascular event rates [49]. The decrease in cardiovascular risk factors namely lipid profile and blood pressure in our study might contribute to the overall decrease in diabetes and cardiovascular mortality in psoriasis patients with MS.

Increased risk of bladder cancer with the long term use of pioglitazone as shown in French cohort study [50], UK nested case control study [51] and interim results of longitudinal study [52]. However, the 10-year final analysis of longitudinal study [52] did not show any statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone [53]. Similarly, no statistically significant association was found in two Taiwanese studies [54, 55]. Infact, TZDs have shown to decrease the risk of breast, brain, colorectal, ear-nose-throat, kidney, liver, lung, lymphatic, prostate, stomach and uterus cancer significantly [56]. FDA although issued a safety warning, has not withdrawn the drug.

There are no significant differences in metformin as compared to pioglitazone with regard to improvement in psoriasis and MS parameters. But there is significant reduction in weight with the use of metformin and due to controversy of increased risk of bladder cancer associated with pioglitazone; metformin can be preferred over pioglitazone in psoriasis patients with MS.

In subgroup analysis, 10 % of patients in placebo, 14.3 % in metformin and 37.5 % of patients in pioglitazone subgroup had no decline or rather increase in the levels of IL-6 and TNF-α, consistent with the relapse of psoriasis in these patients in next 6 months. Remitting relapsing nature of the disease might be accounted for no significant change in the IL-6 and TNF-α level.

Randomization and placebo control are the strengths of our study. The study also has some limitations. Intermediate dose of pioglitazone (30 mg/day) and metformin (1000 mg/day) was used in the study. Secondly, it was an open label study, although blinded end point assessment was done.

Insulin sensitizers have shown improvement in the parameters of MS as well as psoriasis disease. With further evaluation in clinical studies, Insulin sensitizers can be used for the management of psoriasis patients with MS.