2015/10/21 DRUG EVALUATION Diabetes Management Pioglitazone: lessons and learnings 15 years since launch and beyond Oded Stempa* Practice points ● Thiazolidinediones (TZDs) or glitazones are PPARγ receptor agonists. ● The primary action site for TZDs is adipose tissue due to high PPARγ concentration. During the early development of TZDs, the primary focus of efficacy studies was their lipid effects. Carbohydrate metabolic effects were discovered incidentally during this period. Stempa ● The first TZD that came on the market was troglitazone; withdrawn 3 years later due to hepatotoxic effects. ● Binding of TZDs with the PPARγ receptor leads to a cascade of intracellular molecular phenomena. Through 415 transactivation and transrepression mechanisms, several genes’ transcription can be either stimulated or inhibited, yielding a varied clinical response. 429 ● Pioglitazone is a TZD with a half-life of approximately 9 h. It has a low distribution volume since it is protein-bound in the blood stream (97%). It is metabolized through the liver CYP450 system. 10.2217/ ● Pioglitazone’s effect on increasing insulin sensitivity has been shown using various methods, followed by dmt.15.38 glycosylated hemoglobin AIc reductions that varied from -0.78 to -1.7% as monotherapy. ● Among other efficacy endpoints described for pioglitazone, a reduction in free fatty acids as well as high sensitive © 2015 FUTURE MediciNE Ltd C-reactive protein has been documented. Several studies have proven a reduction in triglyceride levels with some increase in high density lipoprotein cholesterol concentrations, improved liver histology in patients with fatty liver disease and clinical benefit in women with polycystic ovary syndrome. Pioglitazone: lessons & learnings 15 years since ● There is evidence for anti-inflammatory effects of pioglitazone at the endothelial level, as well as a decrease in serum launch & beyond inflammatory markers which may also render some potential benefit from a cardiovascular standpoint, except for those patients who suffer from congestive heart failure, in whom pioglitazone is contraindicated. 5 ● Several safety concerns have accompanied pioglitazone since it was introduced into the market. The most frequent side effects are weight increase and fluid retention that can worsen congestive heart failure. It has been established that bone fracture risk exists only in women with other risk factors for fragility fractures. Supported by a robust body of evidence, bladder cancer risk associated with pioglitazone use is less likely and is currently contraindicated only in 6 patients with previous history of bladder cancer. ● Pioglitazone, a PPARγ agonist, causes significant increments in insulin sensitivity not only in fat and muscle tissue, but 2015 also in the liver, resulting in an improvement in glycemic control in patients with Type 2 diabetes. ● Pioglitazone’s pleiotropic effects on fatty liver disease and endothelial function make it an attractive therapeutic alternative for patients with Type 2 diabetes and insulin resistance (metabolic syndrome). DMT ● Diabetes Manag. Clinical judgment must be used in finding a balance between gains and side effects while selecting patients to be Diabetes Management treated with pioglitazone. 1758-1907 1758-1915Future Medicine LtdLondon, UK *Eli Lilly & Company of Mexico, S.A. of C.V., Barranca del Muerto 329, 1st Floor, Col. San José Insurgentes, Del. Benito Juárez 03900, DF Mexico; Tel.: +52 55 17194544; Fax: +52 55 52722419; [email protected] part of 10.2217/dmt.15.38 © 2015 Future Medicine Ltd Diabetes Manag. (2015) 5(6), 415–429 ISSN 1758-1907 415 D RUG EVALUATION Stempa Pioglitazone is a PPARγ agonist that is widely used as an oral antihyperglycemic agent. Its main effect consists of blunting insulin resistance in tissues such as muscle, liver and adipose tissue. Its strength in terms of glycosylated hemoglobin AIc reduction varies within a range of -1.0 to -1.5%. This article examines the role of pioglitazone in the treatment of Type 2 diabetes mellitus and assesses efficacy data on insulin sensitivity and glycemic control, as well as the effects on hepatic steatosis, endothelial function and cardiovascular risk. Finally, concerns linked to pioglitazone use, such as weight gain, fluid retention, bone fragility, bladder cancer and macular edema, are analyzed finding that pioglitazone use must be balanced between the risks and benefits for each individual patient. K EYWORDS Thiazolidinediones metabolized through the hepatic CYP450 sys- • glitazone • insulin In the context of the pathophysiological com- tem. Its absorption is rapid and its concentra- resistance • pioglitazone plexity of Type 2 diabetes mellitus (T2DM), tions are measurable in serum up to 30 min after • rosiglitazone insulin resistance must be understood as an dosing [2]. Even though pioglitazone’s half-life • thiazolidinedione essential mechanism for the development and is approximately 9 h, its effect is prolonged due • troglitazone • Type 2 maintenance of this disease. Organ dysfunction to the presence of two active metabolites (M-III diabetes mellitus in T2DM is caused in part by a great amount and M-IV). The mean absolute bioavailability of of free fatty acids (FFAs) in the circulation and pioglitazone is 83% and the time to reach maxi- other inflammatory substances, originating from mum plasma concentration (tmax) is 1.5 h (range: intra-abdominal adipose tissue, which is subject 0.5–3.0). Food intake may discretely delay tmax. to constant lipolysis and turnover. The first PPAR The average clearance is 2.4 l/h (range: 1.72– to be described was PPARγ. The principal media- 4.17) [2]. After single oral doses between 2 and tors in lipogenesis, these receptors interact with 60 mg, both the maximum concentration (Cmax) transcription factors that can stimulate or inhibit and the area under the curve (which indicates the synthesis of certain proteins involved in both systemic exposure) show lineal, dose-dependent the biochemical machinery responsible for the increases without any changes after repeated intracellular management of glucose and in the dosing of the drug. Its distribution volume is inflammatory pathways at the systemic level. low (0.253 l/kg), most probably because more Thiazolidinediones (TZDs), or glitazones, are than 97% of the drug is protein bound [2]. Its molecules that exhibit agonist actions on PPARγ metabolism through the liver’s CYP450 system’s receptors. Initially, their development sought isoenzymes is carried out primarily by oxidation reductive effects on lipids without a clear under- and hydroxylation of methylene groups, resulting standing of their mechanism of action. The first in the presence of several metabolites. A minimal of these drugs, ciglitazone, was never marketed proportion of intact pioglitazone may be detected due to several toxicity findings during its clini- in urine. Its elimination is primarily biliary and cal research program [1] . The effects of TZDs through feces. Drug interactions are presumed to on carbohydrate metabolism were subsequently be low since the induction or inhibition of P450 described and the first of these drugs to be mar- enzymes involved in the metabolism of pioglita- keted was troglitazone in 1997. In 2000, it was zone by other drugs has not been observed [2]. recalled due to toxic effects on hepatic function. Finally, no differences in pioglitazone’s pharma- cokinetic profile were observed between healthy Pioglitazone subjects and patients with T2DM. As regards ●●Pharmacokinetic profile subjects with renal insufficiency, no pharma- Pioglitazone administered once daily regardless cokinetic changes requiring dose adjustments of food intake is well absorbed and subsequently were observed. However, a decrease by around 57% in the Cmax was observed in patients with liver failure, while the distribution volume was O N O increased (Figure 1) [2]. S NH H3C ●●Clinical efficacy: effects on insulin OH O resistance & glucose metabolism Through its transactivation and transrepression mechanisms, several effects of pioglitazone on Figure 1. Chemical structure of pioglitazone. insulin sensitivity, fasting plasma glucose (FPG) 416 Diabetes Manag. (2015) 5(6) future science group Pioglitazone: lessons & learnings 15 years since launch & beyond D RUG EVALUATION and glycosylated hemoglobin A1c (HbA1c) con- The observed decrease in systemic inflam- centrations have been described, along with its mation markers such as high sensitivity CRP effects on other metabolic parameters, especially supports the anti-inflammatory role of TZDs as lipid profile. they inhibit the release of inflammatory media- Pioglitazone decreases insulin resistance, as tors by adipose tissue and increase the synthesis shown in 26 therapy-naive patients with T2DM and release of adiponectin [11] . randomly assigned to receive pioglitazone or The activation of PPARγ receptors by pio- intensive nutritional therapy for 6 months. glitazone involves the need for a faster FFA Before and after follow-up, a muscle biopsy was uptake by fat cells. This explains the decrease performed (vastus lateralis) as well as an eugly- in FFA plasma concentrations, the improvement cemic–hyperinsulinemic clamp (80 mU m[-2] in insulin sensitivity in muscular and adipose min[-1]) [3]. Upon completion of the trial, the tissue and the decrease in the lipotoxic effect on most notable observations were statistically sig- β cells [12] . Both the decrease of insulin resistance nificant decreases in FFA plasma concentrations,