The effect of pioglitazone on weight, lipid profile and liver enzymes in type 2 diabetic patients

Abstract

Background:

Pioglitazone is one of the antidiabetic agents used in the management of type 2 diabetes mellitus (DM). The effect of pioglitazone on blood glucose, lipid profile, liver enzymes and weight has been shown with conflicting results. In this study we aim to evaluate the effect of pioglitazone on the weight, lipid profile and liver enzymes in patients with DM.

Methods:

In this single-arm clinical trial, 110 poorly controlled diabetic type 2 patients (63.6% female with mean age of 54.26 ± 8.96 years) who were on maximal dosage of metformin and glibenclamide were enrolled. Patients were treated with pioglitazone for 3 months and laboratory. Fasting blood sugar (FBS), haemoglobin A1C (HbA1C), cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), alkaline phosphatase (ALK-P), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and weight changes were measured before and at the end of the study.

Results:

The levels of FBS (p < 0.001), HbA1c (p < 0.001), triglyceride (p = 0.001), ALT (p = 0.005) and ALK-P (p = 0.001) were significantly decreased, but weight was significantly increased (p < 0.001) after the intervention. There were no significant difference in cholesterol, LDL and HDL values before and after study.

Conclusion:

Although pioglitazone causes a significant decrease in FBS, HbA1C and triglyceride levels, it is associated with weight gain, which would limit its utility.

IRCT registration code: IRCT201209276712N2

Introduction

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by raised glucose levels which is associated with macrovascular and microvascular complications as well as dyslipidaemia, that increase morbidity and mortality [Erlich et al. 2013; Krauss, 2004]. There are various medications introduced to reduce glucose levels and improve DM patients’ clinical status. Pioglitazone, a thiazolidinedione derivative, is an insulin-sensitizing agent developed for the treatment of T2DM [Zenari and Marangoni, 2013; Zou and Hu, 2013]. Pioglitazone is a peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist which can reduce insulin resistance in liver, muscle and adipose tissue [Gross and Staels, 2007; Waugh et al. 2003; Zou and Hu, 2013] and improve glucose and lipid metabolism [Bajaj et al. 2004; Miyazaki et al. 2002].

Pioglitazone treatment in T2DM results in improving lipid profile including decrease in triglycerides and low-density lipoprotein (LDL), increase in high-density lipoprotein (HDL) and decrease in serum fatty acids [Aghamohammadzadeh et al. 2010; Chawla et al. 2013; Razavizade et al. 2013] as well as improved liver function tests [Belfort et al. 2006; Razavizade et al. 2013; Sanyal et al. 2010]. Unlike these findings, other studies were not able to demonstrate any significant improvement in liver function tests [Chawla et al. 2013] or lipid profile [You et al. 2010]. Unlike its beneficiary effects, weight gain is one major side effect of this medication [Defronzo et al. 2013; Nafrialdi, 2012].

Previous reports indicate that compared with glibenclamide or metformin, pioglitazone alone or in combination with any of these agents could reduce blood glucose further [Ceriello et al. 2005]. However, there are controversies in reported effects of pioglitazone. So, it is important to define the exact role of pioglitazone on diabetes control, lipid profile, liver function and possible weight gain. In this study, we aim to evaluate the effect of pioglitazone in Iranian patients with T2DM.

Materials and methods

In this single-arm clinical trial, 110 patients aged 35–75 years with uncontrolled diabetes mellitus and no previous history of taking thiazolidinediones, who were on maximum dose of metformin (1.5–2 g) and glibenclamide (15–20 mg) for at least 1 month, having HbA1c 7.5–11% and fasting blood sugar (FBS) ⩾140 mg/dl were enrolled. Patients with significant renal, cardiac, liver, lung, or neurological disease, anaemia, systemic glucocorticoid therapy patients receiving β-blockers, prior use of or known allergy to any type of available thiazolidinediones, patients currently pregnant, breastfeeding, smokers, and subjects who abused alcohol or drugs and those with a body mass index (BMI) greater than 40 kg/m² were excluded from this study. Subjects were also excluded if they had been treated with insulin or had started treatment with a statin or any fibric acid derivative within 2 months of the beginning of the study. This study was approved by the Ethics Committee of Tabriz University of Medical Sciences and written informed consent was obtained from all patients.

All patients underwent a complete laboratory survey including FBS, lipid profile including cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), alkaline phosphatase (ALK-P), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the weight of patients were assessed at the time of laboratory survey. Then the pioglitazone at a dose of 30 mg was added to the treatment protocol of all patients and they were followed up for 3 months. All above-mentioned laboratory investigations and weight assessing were repeated after 3 months and the obtained data before and after therapeutic intervention were studied.

Data analysis

All data were analysed using the Statistical Package for Social Sciences, version 17.0 (SPSS, Chicago, Illinois). Baseline data are reported as mean ± standard deviation (continuous data) or percentages (categorical data), depending on the data level. To compare the results before and after the intervention, paired t test was used for statistical analysis. A p value of 0.05 or less was considered significant.

Results

In this study, 110 patients with type 2 DM including 70 (63.6%) females and 40 (36.4%) males with a mean age of 54.26 ± 8.96 years were studied.

Table 1 shows the laboratory findings before and after the intervention. As the table shows FBS, HbA1c, TG, ALT, ALK-P were significantly decreased and patients’ weight was increased following intervention. However, no significant differences were observed in the level of cholesterol, HDL, LDL and AST before and after the intervention. Mean percentage of increase in weight was 1.07 ± 0.29%.

Table 1.

Demographic and anthropometric findings between groups.

Variable	Before intervention	After intervention	p value
FBS (mg/dl)	221.01±46.61	146.24±46.61	<0.001
HbA1C (%)	8.51±1.54	7.29±0.90	<0.001
Cholesterol (mg/dl)	156.93±27.16	155.55±29.26	0.61
Triglyceride (mg/dl)	165.15±72.35	145.83±67.19	<0.001
LDL (mg/dl)	80.38±23.19	82.28±23.35	0.42
HDL (mg/dl)	43.60±10.19	44.39±9.77	0.34
AST (IU/ml)	21.49±8.65	21.45±8.16	0.95
ALT (IU/ml)	26.74±13.19	23.66±12.29	<0.005
ALK-P (IU/L)	190.41±63.29	173.62±57.05	<0.001
Weight (kg)	76.78±11.40	77.60±11.79	0.000

FBS, fasting blood sugar; HbA1C, haemoglobin A1C; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ALK-P, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Discussion

In this study, we evaluated the effect of adding pioglitazone to T2DM patients’ treatment protocol which showed significant improvement in FBS and HbA1c as well as triglyceride and ALT levels. The consistent decrease of blood glucose and HbA1C indicates the efficacy of pioglitazone in controlling glycaemia.

Similar findings were found in our previous study about the effects of pioglitazone in T2DM patients [Aghamohammadzadeh et al. 2010]. Improvement in glycaemia control following pioglitazone use had been demonstrated previously [Al-Azzam et al. 2012; Lee et al. 2013; Nafrialdi, 2012; You et al. 2010]. It is reported that pioglitazone causes a reduction in insulin resistance and reduces fasting plasma insulin levels that will result in improved glycaemia control [Pavo et al. 2003].

In patients with type 2 diabetes, there is a strong association between high triglyceride and low HDL levels and cardiovascular morbidity and mortality [Pfützner et al. 2011]. We also observed that pioglitazone caused significant reduction in triglyceride levels, but has no significant effect on cholesterol, HDL and LDL. Previous studies have shown significant reduction in triglyceride as well as increase in HDL, but the changes in LDL and cholesterol levels were not significant [Aghamohammadzadeh et al. 2010; Chawla et al. 2013; Razavizade et al. 2013]. Unlike these findings, You and colleagues found significant decrease in total cholesterol and LDL levels, but the decrease in triglyceride and HDL levels were not significant [You et al. 2010]. This difference may be due to the longer duration of drug treatment in different studies as well as medication doses, patients’ heterogeneity (considering weight, gender, daily physical activity).

It is shown that pioglitazone can prevent inflammatory process and in result, improve liver function [Razavizade et al. 2013; Sanyal et al. 2010]. Sanyal and colleagues showed that the consumption of pioglitazone compared with placebo significantly reduced the serum levels of AST and ALT [Sanyal et al. 2010]. Belfort and colleagues also observed significant reduction in AST and ALT levels following pioglitazone therapy in patients with nonalcoholic steatohepatitis [Belfort et al. 2006]. In our study, we observed significant reduction in ALT and ALK-P, but no changes were seen in AST levels indicating that pioglitazone is not harmful for the liver. However, Chawla and colleagues observed no improvement in liver function test [Chawla et al. 2013]. We suggest that the differences in the results might be due to the variations in the studies duration, patients’ characteristics and medication dosage. However, the existence of controversy in their effect on ALT and AST levels are the main concerns that need complementary investigations.

ALT and AST serve as a marker of hepatocyte injury. Chronic mild elevation of these transaminases is frequently found in type 2 diabetic patients. Loss of insulin effect on the liver leads to glycogenolysis and an increase in hepatic glucose production. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues such as the liver are an early manifestation of conditions characterized by insulin resistance and are detectable earlier than fasting hyperglycaemia. Insulin resistance is proposed to lead to fatty changes in the liver. The excess in free fatty acids found in the insulin-resistant state is known to be directly toxic to hepatocytes and thus increasing ALT and AST. Also, proinflammatory cytokines are increased during insulin-resistant state which also contributes to hepatocellular injury [Grove et al. 1997; Neuschwander-Tetri and Caldwell, 2003]. It is possible that thiazolidinediones including pioglitazone improve the liver function tests by their role in improving in insulin sensitivity and their anti-inflammatory effects [Browning and Horton, 2004].

Weight gain is a major problem that limits pioglitazone use [Chawla et al. 2013; Sanyal et al. 2010]. Similar to previous findings [Chawla et al. 2013; Nafrialdi, 2012; Sanyal et al. 2010], we observed significant increase in patients’ weight following pioglitazone use. However, this increase was only 1.07%. Some previous studies have reported an increase of 5% in body weight after pioglitazone use [Chawla et al. 2013; Nafrialdi, 2012; Sanyal et al. 2010]; however, similar to our findings, Pavo and colleagues found lower weight increase (0.9%) following pioglitazone use [Pavo et al. 2003]. Unlike all of these findings, You and colleagues did not find weight gain following pioglitazone use [You et al. 2010]. It is believed that increased body weight is due to water retention and fat accumulation [Derosa, 2010; Pendsey et al. 2002; Yki-Järvinen, 2004]. Although many studies have shown that pioglitazone may cause weight gain but some of them demonstrated that a proper diet may prevent this side effect in diabetic patients taking pioglitazone for more than 16 weeks [Ditschuneit, 2006]. Also, Fonseca in his study showed that pioglitazone may cause weight gain but adherence to a proper diet can attenuate this effect [Fonseca, 2003].

Although pioglitazone improved glucose and reduced HbA1c in diabetic patients, but could not fully improve the lipid profile and it was associated with weight gain. Therefore, other therapeutic interventions such as a proportional weight loss control diet must be accompanied with this therapeutic intervention in order to optimize the effectiveness of these drugs.

It is reported that different ethnicities in different regions have different outcome and response to the same endocrine disease despite similar or even lower incidence of the disorder [Golden et al. 2012], so the treatment protocol, the dosage of treatment used and the observed outcome varies between different ethnicities. It is also shown that even various ethnicities in a same geographical region demonstrate different symptoms and outcome [Chong et al. 2009]. Previous studies have also shown that each ethnicity and racial group differs in severity of the insulin resistance [Spanakis and Golden, 2013]. So, it is possible that the observed effects of pioglitazone in our study which are different from other studies could be due to racial and ethnical differences between studies. It should be noted that the observed results are among the patients with T2DM in Iran and it is possible that the observed differences, especially in lipid profile, could be due to this.

Limitations

This study had some limitations. We did not have a control group, so could not exactly compare the changes observed in lipid profile, glycaemia control, liver function and weight gain, as it is possible that some of these changes occur even without pioglitazone use. We did not evaluate patients’ physical activity which limits the findings on weight gain. We also did not put patients on a similar diet. This may be another limitation, as the diet used has significant effects on the evaluated variables. Most studies have treated patients for longer time (more than 40 weeks) and evaluated the long-term use of pioglitazone; the short period of treatment and follow up in our study is another limitation. However, we performed the study to show early beneficiary results of pioglitazone treatment.

Conclusion

It is concluded that pioglitazone is a good antidiabetic agent in patients with T2DM who do not respond properly to maximum dose of glibenclamide and metformin. This agent has no negative impact on lipid profile and liver function tests but carries a trivial risk of weight gain which would limit its utility.