Effects of Tumor Necrosis Factor α Inhibitors Extend Beyond Psoriasis: Insulin Sensitivity in Psoriasis Patients With Type 2 Diabetes Mellitus

Statistical analysis was performed using SPSS software (version 12.0). Continuous patient characteristics were analyzed using mean and SD as well as discrete data as counts and proportions. Association was examined using χ² tests for categorical variables and 2-sided t test/Wilcoxon rank sum test for continuous variables. Analysis of variance was used to compare the results in 3 different anti-TNF agents used in the study group.

Results

Of the 35 participants enrolled in the study group, 34 (97.1%) completed the study and were evaluated. The study group included 16 men and 18 women aged 19 to 63 years (mean age [SD], 43.7 [21.6] years) who were treated with TNF-α inhibitors—8 participants with etanercept, 14 with adalimumab, and 12 with infliximab—according to the standard dosage schedule for 24 weeks.

Of the 35 participants enrolled in the control group, 29 (82.9%) completed the study and were evaluated. Six patients did not follow up for the complete duration of the 24-week study period and were not evaluated. The control group included 14 men and 15 women aged 18 to 65 years (mean age [SD], 47.7 [14.2] years) who were treated with other systemic therapies—8 participants with topical corticosteroids or calcipotriol only, 7 with cyclosporine A, and 14 with methotrexate. The dose of the drug was kept stable throughout the 24-week study period.

Demographic and baseline characteristics for all participants are shown in Table 1. There were no significant differences in demographic or baseline characteristics among the study group versus the control group, and all participants were similar in age; body mass index; as well as FPG, fasting insulin, and HbA_1C levels.

At baseline, both study and control participants had elevated mean (SD) FPG levels (10 [25] mmol/L and 11 [0.4] mmol/L, respectively), fasting insulin levels (2.79 [0.17] pmol/L and 2.82 [0.13] pmol/L, respectively), and HbA_1C levels (8.4% [0.38%] and 8.1% [0.21%], respectively)(Table 1).

The study group showed significant improvements in glycemic control at the end of the study (Table 2). At week 24, study group participants had a mean (SD) decrease in FPG levels of 2.74 (0.34) mmol/L versus 0.02 (0.16) mmol/L in the control group. This difference between the 2 groups after 24 weeks was found to be statistically significant (P<.01). On further analysis of the study group, no statistically significant difference (P>.01) was noted in the 3 anti-TNF agents used. Compared to the control group, the study group showed a significant decrease from baseline values of FPG and HbA_1C (P<.01). Fasting insulin levels decreased significantly for study group participants as compared with control (–1.91 pmol/L vs 0.04 pmol/L)(P<.001)(Table 2). However, on analysis of the 3 anti-TNF agents, no statistically significant difference was found (P>.05). Participants in the control group showed no significant change in fasting insulin and FPG levels.

To confirm that there was a change in insulin sensitivity in response to TNF-α inhibitors, we analyzed FPG and fasting insulin values using the HOMA method. There was no change in mean relative insulin resistance in the control group in response to therapy (mean [SD], 5.4 [0.31] vs 5.6 [0.15], before vs after therapy), while there was mild improvement in relative insulin resistance in the study group (5.9 [0.52] vs 4.8 [0.34], before vs after therapy). There also was a significant difference in the change in relative insulin resistance in response to treatment between the study and control groups (1.2 [0.40] vs –0.3 [0.12]; P<.01)(Table 2).

Comment

There has been an unprecedented rise in the rate of obesity and associated metabolic diseases such as type 2 DM. Following the current trend, it is estimated that the world will have approximately 592 million cases of type 2 DM by the year 2035.¹⁹ Almost two-thirds of these patients are estimated to die of cardiovascular diseases.

Although the pathophysiology of type 2 DM is not known, insulin resistance in the muscles and liver as well as failure of pancreatic β cells represent the core of the complex pathophysiology. The associated underlying silent inflammation was thought to have a key role in both insulin resistance and insulin secretory defects seen in type 2 DM. Furthermore, recent data suggest the central role of TNF-α, IL-1, and IL-6 pathways in this inflammation.¹⁰ Tumor necrosis factor α has been shown to have a dual effect on insulin resistance as well as pancreatic β cell function. It blocks the function of insulin at the receptor level and has been implicated as a causative factor in obesity-associated insulin resistance and also in the pathogenesis of type 2 DM.^20,21 Furthermore, cytokines that activate nuclear factor κβ (a nuclear transcription factor closely involved in the regulation of cellular inflammatory response), such as TNF-α, are thought to be a common denominator for β-cell apoptosis in types 1 and 2 DM.²² Additionally, it has been suggested that TNF-α is a powerful regulator of adipose tissue.²³ Neutralizing TNF-α in obese Zucker rats has shown increased insulin sensitivity.³ Tumor necrosis factor α and IL-6 as well as C-reactive protein and plasminogen activator inhibitor 1 are negatively associated with insulin sensitivity.^24-27 These findings have led researchers to investigate the role of anti-TNF agents for the management of type 2 DM.²⁸