Prospective Pioglitazone Clinical Trial Research Articles

EMPA-REG and Other Cardiovascular Outcome Trials of Glucose-lowering Agents: Implications for Future Treatment Strategies in Type 2 Diabetes Mellitus

During the last decade, the armamentarium for glucose-lowering drugs has increased enormously by the development of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors, allowing individualization of antidiabetic therapy for patients with type 2 diabetes (T2DM). Some combinations can now be used without an increased risk for severe hypoglycemia and weight gain. Following a request of the US Food and Drug Administration, many large cardiovascular (CV) outcome studies have been performed in patients with longstanding disease and established CV disease. In the majority of CV outcome studies, CV risk factors were well controlled and a high number of patients were already treated with ACE inhibitors/angiotensin receptor blockers, statins and antiplatelet drugs. Most studies with insulin glargine and newer glucose-lowering drugs (saxagliptin, alogliptin, sitagliptin, lixisenatide) demonstrated safety of newer glucose-lowering agents but did not show superiority in the CV outcomes compared with placebo. By contrast, in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study, CV death, all-cause mortality, and hospitalization for heart failure were significantly decreased when empagliflozin was added instead of placebo to therapy for patients with high CV risk and T2DM already well treated with statins, glucose-lowering drugs, and blood pressure–lowering drugs as well as antiplatelet agents. In addition, renal endpoints including endstage renal disease were also significantly reduced when empagliflozin was added instead of placebo. Interestingly, the reduction of these clinically relevant end points was observed after a few months, making antiatherogenic effects an unlikely cause. The fact that the incidence of myocardial infarction (MI) and stroke were not reduced is in line with the hypothesis that hemodynamic factors in particular have contributed to the impressive improvement of the prognosis. To reduce the CV burden of patients with T2DM, drugs influencing factors involved in atherogenesis (eg, insulin resistance, chronic inflammation, increase of HDL, prothrombotic state) are more promising. The recent IRIS (Insulin Resistance Intervention after Stroke) study documented a significant reduction in stroke and MI when pioglitazone instead of placebo was given to nondiabetic patients presenting with both stroke/transient ischemic attack and insulin resistance, confirming results from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study in patients with T2DM. Based on these new data, we suggest that the addition of both empagliflozin and pioglitazone to metformin might be the relative best option to reduce the high CV morbidity and mortality of patients with T2DM and already established CV complications. The very recent announcement that the CV outcome study with liraglutide (LEADER) also demonstrated a significant reduction of the composite endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) gives new hope for further beneficial treatment options for T2DM patients with established CVD.

Pleiotropic Effects of Thiazolidinediones: Implications for the Treatment of Patients With Type 2 Diabetes Mellitus

Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator–activated receptor-γ to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on β-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs–especially pioglitazone–exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, β cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5–30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns.

Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J2012;36:371-8)

Dear Editor, Ever since prospective pioglitazone clinical trial in macrovascular events (PROactive), the very first large randomized trial of pioglitazone, published in 2005 [1], whether this antihyperglycemic agent could increase the risk of bladder cancer was debated by diabetologists and pharmacologists. Despite lack of support from molecular mechanism, several cohorts observed the association between long term application of pioglitazone and the bladder cancer risk [2,3]. Recently, a nested case-control study provided by Azoulay et al. [4] also indicated bladder cancer risk increased 1-fold after 2-year usage of pioglitazone. It appeared no doubt that bladder cancer should be caused by this agent. However, no rational explanation was given by investigators. In the current study by Song et al. [5], an obviously lower prescription of pioglitazone was reported in diabetic patients with bladder cancer compared with those bladder cancer-free ones (6.4% vs. 15%). Interestingly, the adjusted odds ratio (OR) of bladder cancer incidence was 2.09, which was almost the same with previous reports [1-4], despite failed to reach statistical significance in the current population. This result brought us two questions: Why was the prescription of pioglitazone in diabetic patients with bladder cancer so low compared with controls? What made the result of such difference between the results from univariate and multivariate statistics? As the risk of pioglitazone has been reported for years since 2005 [1], diabetologists all over the world may have already noticed the risk of this agent, and have a mind to prevent the usage in real clinical practice if a patient has a high risk of cancer. Furthermore, a potential selective bias could be hardly prevented in the design of matched case-control study. For the second question, it appears that the multivariate model in the study perfectly adjusted for all potential confounding biases, and the adjusted OR just gave the 'true' risk like previous studies. Among the adjusted factors, co-existing neoplasm would a potential bias, and the reason was mentioned above. However, it required further analysis of the original data to determine whether it is really the very one that explained such difference between the results from univariate and multivariate statistics. It could be of interest that might tell us why there was little prescription of diabetic patients with bladder cancer, and help us understand if it is really pioglitazone which lead to the cancer of urinary bladder.

Glycemic control: a combination of lifestyle management and the use of drugs.

Some 30% of contemporary cardiology patients have coexisting known diabetes, and another 40% have either undiagnosed diabetes or prediabetes. There is still no final conclusive evidence of cardiovascular benefit by good glycemic control in type 2 diabetes, although studies like the United Kingdom Prospective Diabetes Study (UKPDS) and the Prospective Pioglitazone Clinical Trial in Macrovascular Events, and meta-analyses based on these and other randomized controlled trials of blood glucose-lowering therapies have been encouraging. On the other hand, microvascular disease is clearly reduced by good glycemic control. Structured education has remained a mandatory prerequisite of any successful treatment. Not only is appropriate weight management by diet and exercise able to revert new onset diabetes to normal, but it is also the foundation of any successful pharmacotherapy of diabetes. Aiming at normal fasting plasma glucose concentrations of 5.3 mmol/L or 95 mg/dL appears to be safe since publication of the long-term outcome results of the Outcome Reduction with an Initial Glargine INtervention trial. Individualized target glycosylated hemoglobin levels as near to normal as safely possible (i.e., <7% and avoiding hypoglycaemia) are the goal for glycemic control. Hypoglycemia seems to emerge as a real concern in cardiology patients. Based on the findings of UKPDS, including the “legacy” study, metformin is the most widely recommended first-line drug therapy in type 2 diabetes, also in terms of preventing cardiovascular complications. An alternate first-line option in some parts of the world, especially Asian countries, is the class of alpha-glucosidase inhibitors. In most patients, combination therapies with two or three classes of drugs are warranted. Early combination are the golden strategy as type 2 diabetes is a multi-causal disease; the various classes of drugs have distinct and synergistic modes of action, and the blood glucose-lowering efficacy of these drugs is more or less fully maintained in combination. The recent joint American Diabetes Association/European Association for the Study of Diabetes position statement mentions five options as step two of the treatment algorithm for combination with metformin: sulfonylureas, pioglitazone, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and basal insulin.

The Cardiologist’s Role in the Management of Type 2 Diabetes—A Review

Evidence-based medicine is key to the cardiologist’s role in the management of type 2 diabetes. Proven therapies that reduce cardiovascular (cV) events with few off-target effects are imperative. evidence from epidemiology studies supports the concept that increased blood sugar is correlated with increased cV events. unfortunately, the lowering of glucose with current agents shows limited benefit in reducing cV events. Metformin in the obese individual reduced cV events and is currently first-line therapy in most clinical practice guidelines. recently, a meta-analysis reported that current hypoglycemic agents did not improve cV outcomes and were possibly harmful. Possible exceptions come from the Prospective pioglitazone clinical trial in macrovascular events (Proactive), a secondary prevention trial in patients with prior myocardial infarction in which pioglitazone was found to reduce cV events. glucagon-like peptide-1 (gLP-1) agonists appear to be the most exciting new cV agents, but a dipeptidyl peptidase-4 (DPP4) inhibitor (sitagliptin) combined with a high-dose angiotensin-converting enzyme inhibitor (Acei) (enalapril) may increase blood pressure and heart rate. Lifestyle modification and proven global risk reduction are still the number one ways to reduce cV events in type 2 diabetes.

Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J2012;36:371-8)

Type 2 diabetes mellitus is characterized by insulin resistance as well as progressive pancreatic β-cell dysfunction. Thiazoli dinediones (TZDs) are a class of hypoglycemic medications that influence insulin sensitivity in peripheral tissue [1]. Piogl itazone is a TZD, peroxisome proliferator-activated receptor (PPAR)-γ ligand used in the treatment of type 2 diabetic patients [2]. Many preclinical trials have demonstrated that PPAR-γ is a potential molecular target for the development of bladder cancer. Yoshimura et al. [3] found PPAR-γ mRNA in bladder cancer samples. Furthermore, immunohistochemistry revealed that the protein expression of PPAR-γ was significantly higher with increasing grade and increasing stage of bladder cancer [3]. In male rats exposed to muraglitazar, a dual human PAPR-α/γ agonist, there was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder [4]. Lubet et al. [5] also reported that another PPAR-γ agonist, rosiglitazone, enhanced bladder tumors in rats pretreated with N-(4-hydroxybutyl)-N-(butyl)-nitrosamine (BBN), a known DNA-reactive bladder carcinogen in several species. However, the mechanisms underlying this pro-tumor potential of pioglitazone for bladder cancer are not fully understood. In the large prospective pioglitazone clinical trial in macrovascular events (PROactive) study, 14 bladder cancers occurred in the pioglitazone arm (0.5%) versus 6 in the placebo arm (0.2%) [6], and in September 2010, the U.S. Food and Drug

The Incretin Axis in Cardiovascular Disease

In 1964, studies in just 2 subjects offered a simple, salient, and fundamental observation reported in 612 words: Glucose induces a greater insulin response when introduced through the gastrointestinal tract than when injected intravenously (the Figure, A).2 This finding built on studies dating to 1928 that injecting extracts of small intestine into animals lowered their glucose levels. Subsequently, this incretin effect was found to be mediated by glucagon-like peptide-1 (GLP1) and its action on pancreatic GLP1 receptors, in addition to contributions from glucose-dependent insulinotropic polypeptide.3,4 Moreover, the incretin response was found to be impaired in those with type 2 diabetes mellitus (T2D). We now know that the incretin axis also includes the enzyme dipeptidyl peptidase-IV (DPPIV), a serine protease that rapidly degrades GLP1 and other proteins.5 Ultimately, this arc of discovery led to new approved antidiabetic therapies: GLP1 analogs (exenatide, liraglutide) and DPPIV inhibitors (saxagliptin, sitagliptin, and, outside the United States, vildagliptin).4 For both classes of drugs, early preclinical experiments and smaller human studies suggest that targeting the incretin axis might address the elusive goal of an antidiabetic agent that improves cardiovascular disease.6,7 In the current issue of Circulation , Shah et al8 add this evolving story with their report that alogliptin, a DPPIV inhibitor in development, limits atherosclerosis and inflammation in 2 different mouse models. Given the increasing clinical use of approved incretin modulators, current large cardiovascular outcome trials with GLP1 agents and DPPIV inhibitors, and ongoing development of novel agents that target incretin signaling, further consideration of how the incretin axis might intersect the cardiovascular system is well warranted. Figure. A , The incretin effect. The well-documented phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma levels of glucose is known as …

Pioglitazone in Combination with Insulin—An Overview of Results from PROactive

Pioglitazone provides one of several add-on therapy options for patients with unsatisfactory glycemic control treated with insulin. Although pioglitazone has the beneficial feature of low hypoglycemia risk, it has an overlapping adverse event profile with insulin in terms of edema (with the potential to exacerbate heart failure) and weight gain, leading to possible concern over their use in combination. Fortunately, subgroup analyses from the Prospective pioglitazone clinical trial in macrovascular events (PROactive) have provided valuable insights into the efficacy and safety profile of pioglitazone in patients on established insulin therapy. Pioglitazone improved glycemic control and lipids, while enabling patients to reduce their insulin requirements. With the combination, edema and weight were predictable with no excess exacerbation of heart failure. Importantly, pioglitazone had a good macrovascular safety profile (with a trend toward benefit), consistent with the overall population. This article provides an overview of the results from the insulin-treated subgroup in PROactive and highlights some of the clinical implications for pioglitazone–insulin combination therapy.

Rosiglitazone: a European regulatory perspective

Abbreviations CHF Congestive heart failure CHMP Committee for Medicinal Products for Human Use EMA European Medicines Agency FDA Food and Drug Administration MAH Marketing authorisation holder PROactive Prospective Pioglitazone Clinical Trial in Macrovascular Events RECORD Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes SAG Scientific Advisory Group of the EMA SPC Summary of Product Characteristics TZD Thiazolidinedione

Pioglitazone use in combination with insulin in the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive19)

2型糖尿病是一种以胰岛素抵抗和胰岛素分泌减少为特征的进展性疾病.磺脲类药物和二甲双胍对β细胞功能均无长期保护作用,许多2型糖尿病患者虽用二甲双胍和磺脲类药物联合治疗,但血糖仍不能达标(HbA1C<7.0%),最终仍需使用胰岛素。

Improving Drug Safety Surveillance

The thiazolidinediones (TZDs) were introduced to the US market in 1997 as therapies to control hyperglycemia in patients with diabetes mellitus. This class of drugs (agonists of peroxisome proliferator-activated receptor γ) has a wide range of biochemical effects, including lowering blood sugar by increasing insulin sensitivity. The TZDs were adopted relatively rapidly and achieved sales of nearly $3 billion in the United States in 2009. Article see p 538 Rapid increases in TZD use occurred despite accumulating safety concerns about the drugs. The first in the class troglitazone was withdrawn from the US market in 2000 because of evidence that it could cause hepatotoxicity that was in some cases lethal. Subsequently, reports emerged that the 2 remaining TZDs available in the United States (pioglitazone and rosiglitazone, both approved in 1999) were associated with substantially higher risks of fluid retention and heart failure, complications of particularly serious consequence in patients with diabetes.1 However, TZD use remained robust, including among patients with important contraindications.2 Further, the 2 currently available TZDs have varied metabolic effects beyond lowering blood glucose, raising questions about their effects on important cardiovascular outcomes. Both agents modestly lower blood pressure but also cause weight gain and raise low-density lipoprotein cholesterol levels. Further, rosiglitazone significantly raises triglyceride and low-density lipoprotein cholesterol more than pioglitazone.3 Hypotheses about the impact of these metabolic effects on health outcomes were merely speculation until larger clinical studies became available. The cardiovascular effects of pioglitazone were studied in the Prospective Pioglitazone Clinical Trial in Macrovascular Events, a placebo-controlled clinical trial. Although the study had negative findings with respect to the primary composite cardiovascular outcome, a principal secondary end point of death and selected cardiovascular outcomes was significantly improved in patients receiving pioglitazone.4 Although this study was considered by many as inadequate evidence …

Strict glycaemic control in diabetic patients with CKD or ESRD: beneficial or deadly?

The evidence in CKD Information about the effect of strict glycaemic control on outcome in diabetic patients with CKD is very limited. In the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events), patients with type 2 diabetes and CKD (n = 597; 11.6% of the 5154 patients) had a particularly high CV risk and cardiovascular disease (CVD) [7]. The incidence of the combined end point (non-fatal myocardial infarction, stroke and death) was 18.3% in patients with CKD compared with 11.5% in patients without CKD (HR 1.65; P < 0.0001). In addition, all-cause mortality was 10.9% compared to 5.9% (HR 1.86) in those without CKD. Remarkably, patients who had CKD and were treated with pioglitazone were less likely to reach the combined end point (HR 0.66; P < 0.001) independently of the severity of renal impairment [7]. Since at study end the HbA1c difference between pioglitazone and placebo was only 0.5% (6.9 vs 7.4%), presumably a variety of well-documented anti-atherogenic effects of pioglitazone [8] were responsible for CV protection in diabetic patients presenting with CVD.

Pioglitazone Use in Combination with Insulin in the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive19)

In this post hoc analysis, we examined insulin requirements and regimens, glycemic control, cardiovascular outcomes, and safety in the patients treated with insulin at baseline in the Prospective Pioglitazone Clinical Trial in Macrovascular Events study. The Prospective Pioglitazone Clinical Trial in Macrovascular Events study was a double-blind, placebo-controlled outcome study (mean follow-up 34.5 months) in 5238 high-risk patients with type 2 diabetes randomized to pioglitazone (force titrated to 45 mg) or placebo. One third of the total population (pioglitazone 864; placebo 896) were receiving insulin at baseline. A rapid and sustained decrease in insulin dose was observed with pioglitazone vs. a progressive increase with placebo. By study end, the mean insulin dose was lower with pioglitazone (42 vs. 55 U/d with placebo; P < 0.0001). The insulin regimen (number on insulin, need for multiple injections, and reduction in oral agents) had been simplified vs. placebo; nevertheless, a greater glycosylated hemoglobin reduction was observed with pioglitazone (-0.93%) vs. placebo (-0.45%; P < 0.0001). At the final visit, insulin had been discontinued in 9% of pioglitazone vs. 2% of placebo patients (P < 0.0001). More insulin-resistant patients (defined as poorly controlled type 2 diabetes despite high doses of insulin) in the pioglitazone plus insulin group showed the greatest glycosylated hemoglobin decline. There were nonsignificant reductions with pioglitazone relative to placebo in the cardiovascular primary (hazard ratio 0.86; 95% confidence interval 0.71, 1.04; P = 0.1198) and main secondary (hazard ratio 0.85; 95% confidence interval 0.67, 1.08; P = 0.1831) end points in insulin-treated patients. The rates of overall heart failure, edema, and hypoglycemia were higher with pioglitazone [13.5 vs 10.5% (P = 0.0489); 30.8 vs. 18.2% (P < 0.0001); and 42.1 vs 29.0% (P < 0.0001), respectively], but there were no significant differences in serious events. Pioglitazone use in combination with insulin resulted in a sustained improved glycemic control and allowed the treatment regimens to be simplified and the insulin doses reduced.

Long‐term glycaemic effects of pioglitazone compared with placebo as add‐on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18)

To assess the long-term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of > or = 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose-lowering therapies. In a post-hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add-on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow-up averaged 34.5 months. There were significantly greater reductions in glycated haemoglobin (HbA(1c)) with pioglitazone than with placebo and more pioglitazone-treated patients achieved HbA(1c) targets, irrespective of the baseline oral glucose-lowering regimen and despite a decrease in the use of other glucose-lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.

Evidence for the Importance of Adiponectin in the Cardioprotective Effects of Pioglitazone

The favorable effects of the peroxisome proliferator-activated receptor-gamma ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)-induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-beta1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II-induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II-infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II-induced pathological cardiac remodeling via an adiponectin-dependent mechanism.

Long-Term Lipid Effects of Pioglitazone by Baseline Anti-Hyperglycemia Medication Therapy and Statin Use from the PROactive Experience (PROactive 14)

Studies have shown that pioglitazone treatment in patients with type 2 diabetes mellitus can improve parameters of diabetic dyslipidemia. The aim of this study was to examine the effect of pioglitazone on triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels in patients from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) to determine whether pioglitazone-induced lipid effects were altered by different baseline antihyperglycemia medication or statin use. PROactive was a long-term, randomized, double-blind, cardiovascular outcomes study in patients with type 2 diabetes at high cardiovascular risk who had pioglitazone or placebo added to existing treatment. The present post hoc study analyzed lipid results from patients who received different baseline antihyperglycemia regimens and the presence or absence of baseline statin use. Independent of antihyperglycemia medication and statin use, triglyceride levels decreased in all subgroups treated with pioglitazone (-9.9% to -12.3%), whereas little change was observed in placebo groups. High-density lipoprotein cholesterol increased nearly twice as much with pioglitazone (18.1% to 20.3%) as with placebo (8.1% to 11.8%) across all subgroups. Low-density lipoprotein cholesterol increased moderately with pioglitazone (5.2% to 9.6%) compared with placebo (3.3% to 7.6%) (placebo-adjusted range 1.11% to 4.37%). In conclusion, long-term pioglitazone therapy led to durable improvements in triglyceride and high-density lipoprotein cholesterol levels, irrespective of baseline antihyperglycemia therapy or statin use.

Current Therapeutic Drugs for Type 2 Diabetes, Still Useful After 50 Years?

Current Therapeutic Drugs for Type 2 Diabetes, Still Useful After 50 Years?

Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective

BackgroundThe aim of this study was to project health-economic outcomes relevant to the German setting for the addition of pioglitazone to existing treatment regimens in patients with type 2 diabetes, evidence of macrovascular disease and at high risk of cardiovascular events.MethodsEvent rates corresponding to macrovascular outcomes from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study of pioglitazone were used with a modified version of the CORE Diabetes Model to simulate outcomes over a 35-year time horizon. Direct medical costs were accounted from a healthcare payer perspective in year 2005 values. Germany specific costs were applied for patient treatment, hospitalization and management. Both costs and clinical benefits were discounted at 5.0% per annum.ResultsOver patient lifetimes pioglitazone treatment improved undiscounted life expectancy by 0.406 years and improved quality-adjusted life expectancy by 0.120 quality-adjusted life years (QALYs) compared to placebo. Direct medical costs (treatment plus complication costs) were marginally higher for pioglitazone treatment and calculation of the incremental cost-effectiveness ratio (ICER) produced a value of €13,294 per QALY gained with the pioglitazone regimen versus placebo. Acceptability curve analysis showed that there was a 78.2% likelihood that pioglitazone would be considered cost-effective in Germany, using a "good value for money" threshold of €50,000 per QALY gained. Sensitivity analyses showed that the results were most sensitive to changes in the simulation time horizon. After adjustment for the potential stabilization of pancreatic β-cell function with pioglitazone treatment, the ICER was €6,667 per QALY gained for pioglitazone versus placebo.ConclusionThe findings of this modelling analysis indicated that, for patients with a history of macrovascular disease, addition of pioglitazone to existing therapy reduces the long-term cumulative incidence of diabetes-complications at a cost that would be considered to represent good value for money in the German setting.

Cost-effectiveness of pioglitazone in patients with type 2 diabetes and a history of macrovascular disease in a Swiss setting.

To evaluate the cost-effectiveness of pioglitazone versus placebo, given in addition to existing treatment regimens, in patients with type 2 diabetes and evidence of macrovascular disease in Switzerland. Event rates corresponding to macrovascular outcomes from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial of pioglitazone were used to project long-term clinical outcomes as part of a modified version of the previously validated CORE Diabetes Model. Direct medical costs associated with treatment regimens, complications and patient management were accounted in 2005 values based on Swiss-specific unit costs. Time horizon was set to lifetime (35 years). Future costs and clinical benefits were discounted at 2.5% annually in line with Swiss recommendations. One-way sensitivity analyses were performed. Addition of pioglitazone was associated with a reduced incidence of most diabetes-related complications, improved life expectancy (0.258 years) and improved quality-adjusted life expectancy (0.180 QALYs) compared with placebo. Pioglitazone treatment increased direct costs by CHF 10,914 per patient over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) of pioglitazone versus placebo was CHF 42,274 per life-year gained and CHF 60,596 per QALY gained. ICERs were sensitive to variation in time horizon and duration of pioglitazone treatment effects. With a willingness to pay of CHF 80,000 per QALY in the Swiss setting, there was a 62.5% chance that pioglitazone would be cost-effective. Addition of pioglitazone to existing therapy was projected to reduce the long-term cumulative incidence of most diabetes complications and improve quality-adjusted life expectancy. Evaluation of incremental direct medical costs associated with these clinical benefits indicated that pioglitazone is likely to be a cost-effective treatment option in the Swiss setting over patient lifetimes.

Cost-effectiveness of pioglitazone in patients with type 2 diabetes and a history of macrovascular disease in a Swiss setting.

To evaluate the cost-effectiveness of pioglitazone versus placebo, given in addition to existing treatment regimens, in patients with type 2 diabetes and evidence of macrovascular disease in Switzerland. Event rates corresponding to macrovascular outcomes from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial of pioglitazone were used to project long-term clinical outcomes as part of a modified version of the previously validated CORE Diabetes Model. Direct medical costs associated with treatment regimens, complications and patient management were accounted in 2005 values based on Swiss-specific unit costs. Time horizon was set to lifetime (35 years). Future costs and clinical benefits were discounted at 2.5% annually in line with Swiss recommendations. One-way sensitivity analyses were performed. Addition of pioglitazone was associated with a reduced incidence of most diabetes-related complications, improved life expectancy (0.258 years) and improved quality-adjusted life expectancy (0.180 QALYs) compared with placebo. Pioglitazone treatment increased direct costs by CHF 10,914 per patient over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) of pioglitazone versus placebo was CHF 42,274 per life-year gained and CHF 60,596 per QALY gained. ICERs were sensitive to variation in time horizon and duration of pioglitazone treatment effects. With a willingness to pay of CHF 80,000 per QALY in the Swiss setting, there was a 62.5% chance that pioglitazone would be cost-effective. Addition of pioglitazone to existing therapy was projected to reduce the long-term cumulative incidence of most diabetes complications and improve quality-adjusted life expectancy. Evaluation of incremental direct medical costs associated with these clinical benefits indicated that pioglitazone is likely to be a cost-effective treatment option in the Swiss setting over patient lifetimes.