Insulin resistance and beta-cell dysfunction are the two key pathophysiological disorders of diabetes mellitus type 2 (DM T2). The liver, muscle and the adipose tissue are resistant to insulin action. The basal hepatic glucose output is increased, despite the high plasma insulin levels, indicating the presence of hepatic insulin resistance. Increased glucose production by the liver is the primary disorder leading to elevated fasting plasma glucose.
The binding of insulin to the receptor leads to tyrosine phosphorylated insulin receptor and insulin receptor substrate 1 with the subsequent activation of phosphoinositol-3 kinase and Akt. The activation of the insulin-receptor signaling pathway increases the glucose transport into the cell, stimulates glucose phosphorylation and glycogen synthesis, as well as glucose oxidation. The ability of insulin to increase the glucose uptake in peripheral tissues (mainly muscles) is impaired and peripheral insulin resistance is the main cause of postprandial hyperglycemia.
Adipocytes are also resistant to insulin action and the increased lipolysis leads to an increase in plasma free fatty acids. They increase insulin resistance in the liver and muscle, inhibit glycogen synthesis and glucose oxidation, and increase hepatic glucose production. Until DM T2 appears, the insulin resistance of the liver and muscles is compensated by an increased insulin secretion. With time, however, the pancreatic function is affected by reduced beta-cell sensitivity to glucose and beta-cell mass, and plasma glucose concentration rises.
Glucose toxicity and lipotoxicity contribute to the reduced beta-cell secretion. Hyperinsulinemia, by which beta-cells compensate for insulin resistance, stimulates the mitogen-activated protein kinase (MAP) path that suppresses the sensitivity to insulin. The activation of MAP kinase promotes numerous intracellular pathways involved in inflammation, enhances vascular smooth muscle cell growth, and the proliferation and potentiating of atherosclerosis.
Pioglitazone is a medicine from the group of thiazolidinediones (TZDs) – agonists of the peroxisome proliferator activated receptor γ (PPARγ). It is the only thiazolidinedione approved for the treatment of hyperglycemia in DM T2. Pioglitazone is an insulin “sensitizer” which by binding to PPARγ, increases insulin sensitivity of muscle, liver and adipose tissue and decreases plasma glucose in fasting and postprandially.
Pioglitazone is a highly selective PPARγ agonist. PPARγ is a transcription factor, which, when activated by pioglitazone, stimulates the transcription of the insulin-sensitive genes involved in the uptake of fatty acids, as well as of glucose and lipogenesis, and therefore increases or is partially similar to the selective action of insulin. PPARγ is also necessary for normal adipocyte differentiation and proliferation.
PPARγ is expressed in the key target tissues of insulin action, mainly in the adipose tissue, but also in the skeletal muscle, liver, pancreatic β-cells, vascular endothelium, and macrophages. The glucose-lowering effect of TZDs is associated with the increase of the peripheral glucose uptake and the reduction of the hepatic glucose production. TZDs, including pioglitazone, improve insulin signaling and insulin sensitivity in muscle, enhance the production of nitric oxide, a potent vasodilator and anti-atherogenic agent, inhibit the MAP kinase pathway, and reduce the risk of atherosclerosis.
In the liver pioglitazone improves the glucose uptake, decreases the hepatic glucose production by inhibiting gluconeogenesis and reducing fat. Belfort et al. studied 55 people with DM T2 or impaired glucose tolerance with biopsy-confirmed nonalcoholic steatohepatitis. The patients were randomized to a hypocaloric diet or a diet and pioglitazone 45 mg daily. After 6 months of treatment with pioglitazone, the muscle/hepatic insulin sensitivity was improved, the fat content of the liver, objectified by magnetic resonance spectroscopy, was reduced by 54% and the aminotransferase levels were normalized. Liver biopsy showed histological improvement of the steatosis, inflammation, bubble necrosis and fibrosis. Pioglitazone reduces the inflammation expressed by a reduction in the C-reactive protein, the tumor necrosis factor alpha, the transforming growth factor-beta and the increase of adiponectin.
Pioglitazone achieves the positive effects on the metabolism of adipose tissue. By improving the sensitivity to the adipocyte antilipolytic effects of insulin, pioglitazone reduces free fatty acids, which leads to increased insulin sensitivity of the muscle and liver and enhanced insulin secretion. Pioglitazone causes the redistribution of fat from metabolically active visceral fat, associated with increased atherogenesis, to subcutaneous adipose tissue
Miyazaki et al. and studied the effect dose-response to pioglitazone at the doses of 7.5, 15, 30 and 45 mg daily, compared with placebo for 26 weeks in subjects on a poorly controlled diet. Glycated hemoglobin (HbA1c) was significantly decreased at doses of 15 mg (-1.3%), 30 mg (-2.0%) and 45 mg (-3.0%) as compared to placebo (1.2%). The insulin sensitivity, determined by the Matsuda index, improved at all the doses of pioglitazone and the highest – at 45 mg. Hepatic insulin sensitivity index (k/fasting plasma glucose x fasting plasma insulin) was significantly improved. Pioglitazone enhanced the insulin sensitivity of liver, muscle and adipose tissue, which lead to improved glucose and lipid metabolism.
Thiazolidinediones and GLP-1 analogs are the only ones which preserve and enhance the function of beta cells. Pioglitazone was evaluated in a randomized, double-blind, placebo-controlled study of 602 individuals with confirmed through an oral glucose tolerant test / OGTT / impaired glucose tolerance. Observed for 2.6 years, the risk of progression to DM T2 was reduced by 70%.
Pioglitazone significantly improves insulin sensitivity (measured by the Matsuda index and intravenous glucose tolerance test FSIGTT) and the pancreatic beta-cell function as measured by the disposition index (insulin secretion / insulin resistance). In a double-blind, placebo-controlled, 4 month study of poorly controlled patients with DM T2 without medical treatment or who were being treated with a sulfonylurea, pioglitazone significantly improved their beta-cell function. In eight long, > 1.5-year, double-blind placebo-controlled or comparative studies, pioglitazone caused prolonged reduction of HbA1c. This continuous decrease in the glycated hemoglobin could be explained by the storage of the beta-cell function.
Comparative/combination studies with metformin pioglitazone showed equal efficacy in terms of the reduction of glycated hemoglobin and fasting plasma glucose with continuous monitoring. The combination therapy with metformin and pioglitazone had a synergistic effect, leading to significant improvements in the glycemic control by increasing the HDL-cholesterol and decreasing the triglycerides as compared to metformin and placebo.
In comparative studies with sulfonylurea preparation, pioglitazone leads to a similar reduction in HbA1c and fasting plasma glucose. The effect is slower and more prolonged than the earlier effect of the sulfonylurea medicine. Insulin sensitivity, as measured by the homeostasis model (HOMA), shows significant improvement as compared to the treatment with pioglitazone. In combination studies with a sulfonylurea agent, pioglitazone resulted in further significant improvement in the glycemic control, expressed in fasting plasma glucose and HbA1c, as well as in triglycerides and HDL-cholesterol. With a triple combination with metformin, the sulfonylurea preparation achieves further significant improvements of HbA1c. Pioglitazone improves diabetic dyslipidemia, increasing the HDL cholesterol and decreasing the atherogenic small dense LDL-particles and triglycerides.
As monotherapy or in combination with a sulfonylurea agent, metformin or insulin pioglitazone showed a significant reduction in triglycerides and an increase in the HDL-cholesterol. Pioglitazone reduced small dense LDL-particles, regardless of the triglycerides and HDL-cholesterol, which showed that the anti-atherogenic potential of pioglitazone was greater than expected and that it was connected with its effect on the triglyceride, HDL- and LDL-cholesterol alone.
Pioglitazone reduces the total mortality, the nonfatal myocardial infarctions and strokes in people with T2 DM and high risk of macrovascular events.
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was the first prospective, randomized, double-blind, controlled study in patients with DM T2, treated with a diet and/or oral antidiabetic agents and/or insulin with a history of macrovascular disease. It assessed the impact of Pioglitazone on the secondary prevention of cardiovascular events. 5238 patients, representing the typical population at high risk of future macrovascular events, were randomized to pioglitazone titrated from 15 mg to 45 mg (n = 2605) or placebo (n = 2633), in addition to the antihyperglycaemic and symptomatic agents. The observation took 34.5 months. The primary end output (composite of death, myocardial infarction, stroke, amputation of lower limbs, acute coronary syndrome, cardiac bypass or revascularization of lower limbs) was reduced by 10%. The secondary endpoints output (Kaplan-Meier time to death, nonfatal myocardial infarction or stroke) was reduced by 16%.
In a meta-analysis of 19 randomized, double-blind, placebo-controlled or comparative studies involving 16,390 patients treated with pioglitazone, ranging from 4 months to 3.5 years, Lincoff et al. made a systematic assessment of the effect of pioglitazone on ischemic cardiovascular events. The primary end output was the time to total mortality, myocardial infarction and stroke, and the secondary end output – the frequency of heart failure. Death, myocardial infarction or stroke occurred in 375 of 8554 patients (4.4%) who were receiving pioglitazone and in 450 of 7836 patients (5.7%) in the control group. Pioglitazone was associated with a significantly lower risk of death, myocardial infarction and stroke in patients with DM T2.
Two ultrasound studies showed the anatomical regression of atherosclerotic disease treatment with pioglitazone. In the study CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) patients with DM T2 were randomized to pioglitazone or glimepiride for 18 months, and the thickness of the carotid intima media (CIMT) was measured before and after randomization. In subjects treated with pioglitazone SІMT had not progressed (-0.001 mm), while those treated with glimepiride showed significant atherosclerotic progression (+0.012 mm).
In conclusion, pioglitazone provides lasting good glycemic control as mono or combined therapy and improves the cardiovascular prognosis of patients with type 2 diabetes mellitus.
Tchaikapharma High Quality Medicines Inc. manufactures Pioglitazone under the trade name of Pizona.