Effects of Pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: A retrospective review of randomly selected medical records

Boyle, Patrick J.; King, Allen B.; Olansky, Leann; Marchetti, Albert; Lau, Helen; Magar, Raf; Martin, John P.

doi:10.1016/s0149-2918(02)85040-8

Cited by 163 publications

(125 citation statements)

References 45 publications

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“…Taken together, our data add to the results of previous studies >'~5 showing that monotherapy with pioglitazone improves lipid profiles associated with cardiovascular disease in patients with type 2 diabetes mellitus. Such effects may be specific to pioglitazone rather than the thiazolidinedione class as a whole; treatment with another thiazolidinedione, rosigfitazone, has been shown to increase TC, TGs, and LDL-C. [33][34][35] In the present study, the proportion of patients achieving ADA target goals for HDL-C increased after treatment with pioglitazone 30 and 45 mg (statistical significance not assessed), and the proportion of those receiving the 45-mg dose achieving ADA target goals for TGs also increased (statistical significance not assessed), further supporting a role for pioglitazone in ameliorating cardiovascular risk factors.…”

Section: Discussionmentioning

confidence: 99%

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus

Herz

Johns

Reviriego

et al. 2003

Clinical Therapeutics

114

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Objective: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbAlc), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. Methods:Patients with type 2 diabetes mellitus (HbAlc >6.5% and <9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, piogfitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain. Results:A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24-85 years), mean (SD) body mass index was 31.4 (4.8) kg/m 2, mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbAlc by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbAlc of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (>7% to <8%) or high (>8% to <9.8%) baseline HbAlc, both doses of pioglitazone significantly reduced HbAlc (both P < 0.001 vs placebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0,001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0,007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated.Conclusions: In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbAlc, insulin sensitivity, and lipid profile in OAMnaive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia. (Clin Ther.

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Section: Discussionmentioning

confidence: 99%

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus

Herz

Johns

Reviriego

et al. 2003

Clinical Therapeutics

114

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“…As has been demonstrated for ligands of other nuclear receptors, PPAR␥ ligands are not necessarily equivalent in terms of their pharmacological effects in a given organism. For example, pioglitazone has been demonstrated to increase HDL in humans taking this drug as an insulin-sensitizing agent, whereas rosiglitazone lacked this effect (53,54). It has been proposed that at least some of the differential effects of various nuclear receptor ligands are mediated by selective coactivator interactions (28,55,56).…”

Section: Ppar␥ Ligand Identity Determines the Charge Clamp Requiremenmentioning

confidence: 99%

Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor γ

Chin

Wang

et al. 2003

Journal of Biological Chemistry

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The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor ␥ (PPAR␥) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPAR␥ and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPAR␥ is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPAR␥. Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPAR␥ for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.The peroxisome proliferator-activated receptor ␥ (PPAR␥), 1 is a ligand-activated nuclear receptor that plays an important role in adipogenesis and glucose homeostasis (1). Although originally identified as an orphan receptor, PPAR␥ as well as the closely related receptors, PPAR␣ (NR1C1) and PPAR␦ (NR1C2), are believed to bind to a variety of fatty acids and their metabolites (2). Synthetic agonists that activate PPAR␥, such as the thiazolidinediones, rosiglitazone, and pioglitazone, are effectively utilized in clinical practice as "insulin sensitizers" in type 2 diabetics (3). Like other nuclear receptors, PPAR␥ is comprised of several separable functional domains including a constitutively active transactivation domain, AF-1, in the amino-terminal region, a central highly conserved DNAbinding domain composed of two zinc fingers, and a ligandbinding domain (LBD) that contains a ligand-dependent transactivation function, AF-2, in its carboxyl-terminal region (4). PPAR␥ functions as an obligate heterodimer with the retinoid X receptor (RXR) and recognizes specific DNA sequences in the promoter regions of target genes referred to as peroxisome proliferator response elements (PPREs) (5). Once directed to the target gene, the transcriptional activation activity of the receptor is regulated by ligand. Ligand binding leads to a significant conformational change within the LBD that include...

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“…TZDs are contraindicated in patients with liver disease and those with New York Heart Association class III or IV cardiac status. From a therapeutic standpoint, there is likely no significant difference between these agents in terms of glucose-lowering effect [39][40][41][42][43] and they may be slightly less potent than the SUs or biguanides (table 1). This apparent decreased potency may be related to a significant rate of non-responders; however, as when responders are looked at separately, the potency is comparable to other agents (see later).…”

Section: Thiazolidinediones (Tzd)mentioning

confidence: 99%

“…Perhaps the most noticeable of these non-glycemic effects is the ability of the TZDs to raise high-density lipoprotein (HDL) cholesterol by up to 13%. 32,[39][40][41][42][43]46 Furthermore, there may be a differential effect on HDL subtypes with rosiglitazone, preferentially effecting HDL-2 (the most protective HDL subfraction). 46 The effects on triglycerides and low-density lipoprotein (LDL) levels tend to be more variable and there is mounting evidence that pioglitazone performs consistently better in these regards than rosiglitazone.…”

Section: Thiazolidinediones (Tzd)mentioning

confidence: 99%

“…46 The effects on triglycerides and low-density lipoprotein (LDL) levels tend to be more variable and there is mounting evidence that pioglitazone performs consistently better in these regards than rosiglitazone. [39][40][41][42][43] A doubleblind, placebo-controlled, parallel design, phase IV study directly comparing the effects of these two agents on the lipoprotein profile is currently underway. Despite their tendency to increase total LDL cholesterol, the TZDs shift the LDL particle size to larger, less atherogenic molecules, although it is uncertain what this means to overall cardiovascular risk.…”

Section: Thiazolidinediones (Tzd)mentioning

confidence: 99%

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Current Therapeutic Options in Type 2 Diabetes Mellitus: A Practical Approach

Sheehan¹

2003

Clinical Medicine & Research

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The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9 years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of patients with type 2 DM.New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? How long for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin or start a third oral agent? If insulin therapy is started, what should become of the patient's oral agents? How best to explain the patient's weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparing their dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agent will be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A 1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal with in regard to the management of this prevalent and serious disease.

show abstract

Effects of Pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: A retrospective review of randomly selected medical records

Cited by 163 publications

References 45 publications

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus

Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor γ

Current Therapeutic Options in Type 2 Diabetes Mellitus: A Practical Approach

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