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Pioglitazone and cardiovascular risk reduction: time for a second look?

Perdigoto, Ana L.a; Young, Lawrence H.b; Inzucchi, Silvio E.a

Cardiovascular Endocrinology & Metabolism: June 2017 - Volume 6 - Issue 2 - p 55–61
doi: 10.1097/XCE.0000000000000110
Review articles
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Insulin resistance, a fundamental pathophysiological abnormality in patients with type 2 diabetes, is associated with increased cardiovascular (CV) disease risk. In diabetes management, the macrovascular impact of antihyperglycemic agents that do not improve insulin sensitivity has generally been disappointing. In contrast, glucose-lowering drugs that work as insulin sensitizing agents have been postulated to reduce CV complications. The data to support this hypothesis have, however, been inconsistent. The impact of thiazolidinediones on macrovascular events is of particular interest. In this review, we discuss the results of trials reporting CV outcomes in patients treated with thiazolidinediones. We focus on the findings of the recent Insulin Resistance Intervention after Stroke trial that demonstrated a beneficial effect of pioglitazone on CV outcomes in stroke patients with insulin resistance. We discuss the Insulin Resistance Intervention after Stroke results and its implications for clinical practice. We discuss the selective use of pioglitazone as secondary prevention to reduce CV risk in insulin resistant patients.

aDepartment of Internal Medicine, Section of Endocrinology

bDepartment of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence to Silvio E. Inzucchi, MD, Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, 333 Cedar Street FMP 107, PO Box 208020, New Haven, CT 06510-8020, USA Tel: +1 203 737 1932; fax: +1 203 737 2812; e-mail: silvio.inzucchi@yale.edu

Received July 14, 2016

Accepted November 17, 2016

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Introduction

One in three deaths in the USA is attributed to heart disease, stroke, and other cardiovascular conditions 1 (http://www.cdc.gov). Heart disease and stroke are, respectively, the number one and number five leading causes of death in the USA and the first and second leading causes of death worldwide. Diabetes is directly linked to macrovascular complications. Patients with diabetes have a two- to four-fold higher cardiovascular (CV) risk compared with nondiabetic individuals 2–4. The Centers for Disease Control and Prevention estimates that 9.3% of the USA population, 29.1 million people, now have diabetes (http://www.cdc.gov) and, not surprisingly, CV events remain the leading cause of mortality in this population.

Although intensive glycemic control has been shown to reduce the incidence of microvascular complications, such as retinopathy and nephropathy, the impact of glycemic control or specific antihyperglycemic medications on macrovascular complications remains unclear with, apart from a few exceptions, most trials failing to show a clear CV benefit 5,6. The United Kingdom Prospective Diabetes Study demonstrated a significant reduction in myocardial infarction (MI) and mortality over diet therapy in a small subgroup of overweight patients randomized to metformin 7,8. Benefits of metformin on macrovascular disease were also suggested in the HOME trial, which studied a small cohort of type 2 diabetes (T2DM) patients already on insulin 9. The EMPA-REG OUTCOME trial found a significant reduction in CV and all-cause mortality as well as in hospitalizations for heart failure in a large group of patients treated with empagliflozin as compared with placebo, yet events related to atherosclerotic complications appeared unaffected 10. The recently published LEADER trial demonstrated that the rate of first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke in T2DM patients treated with the GLP-1 receptor agonist liraglutide was lower than in placebo treated patients 11. An early report of the SUSTAIN-6 trial alludes to a beneficial effect of semaglutide on major adverse CV events but the actual results have not yet been presented or published as of this writing (http://www.novonordisk.com/media/news-details.2007805.html).

Insulin resistance has also emerged as a risk factor for the development of atherosclerotic complications such as stroke and MI and has been associated with a two- to three-fold increase in CV mortality 12–16. Insulin resistance is present in almost all patients with T2DM and is associated with other conditions such as aging, obesity, polycystic ovarian syndrome, metabolic syndrome, and nonalcoholic fatty liver disease. The pathogenesis of insulin resistance is complex, but is thought to be primarily mediated by impaired insulin signaling that leads to decreased glucose uptake by muscle and fat and increased hepatic glucose production 17,18. The mechanism by which insulin resistance exerts its negative CV effects is not fully understood and is likely multifactorial, related to coexisting hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia, inflammation, hypercoagulation, and endothelial dysfunction 14,19,20.

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Thiazolidinediones

Metformin, a biguanide, and thiazolidinediones (TZDs) are insulin sensitizing drugs used in the management of T2DM. However, metformin is thought to act primarily in the liver to reduce hepatic glucose production and less so through improvement in peripheral insulin sensitivity. TZDs are considered to work predominately in peripheral tissues such as fat and muscle. Pioglitazone is currently the only TZD used to any significant extent. Troglitazone was removed from the market in 2000 because of hepatotoxicity. The use of rosiglitazone has fallen out of favor because of controversial data suggesting increased CV events with this drug (discussed in more detail below).

TZDs are ligands for, and activators of, peroxisome proliferator-activated receptor γ (PPARγ), a pleiotropic nuclear receptor and transcription factor most highly expressed in adipose tissue but also in macrophages, liver, pancreatic β cells, and bone among other tissues 21–23. The mechanism by which TZDs improve insulin resistance is not completely understood but is primarily through effects on adipose tissue, liver, and muscle. PPARγ plays a central role in the differentiation and function of adipose tissue and TZDs act on adipose tissue to regulate adipogenesis and fatty acid oxidation. A ‘lipid steal’ model has been proposed where TZDs promote the ability of adipose tissue to store lipids, decreasing circulating fatty acids, and improving insulin resistance. TZDs increase expression of adiponectin from adipose tissue which may act to reduce liver fat content. They can also directly activate PPARγ in hepatocytes to improve insulin resistance and reduce inflammation. In muscle, TZDs directly or indirectly decrease lipotoxicity and increase insulin sensitivity and glucose uptake. TZDs have proven to be effective in the management of T2DM with a hemoglobin A1c (HbA1c) lowering capacity of about 1% or more, without causing hypoglycemia. They have also been demonstrated to have a more durable glucose-lowering effect over time compared with metformin and glyburide 24. In addition to being efficacious in the treatment of diabetes, TZDs have been shown to delay the progression from prediabetes to T2DM 25,26.

TZDs modify other measures that could presumably influence CV risk. TZDs, in particular pioglitazone, reduce blood pressure, triglycerides, and inflammatory mediators (e.g. C-reactive protein) and increase high-density lipoprotein cholesterol 27–29. Pioglitazone can slow progression of carotid intima media thickness and lead to regression of coronary atherosclerosis 26,30–33 as well as reduce in-stent restenosis in patients with coronary artery disease (CAD) following coronary artery stenting 34,35. Beneficial effects on the development of peripheral arterial disease have also been shown 36,37. Reduction of atherosclerosis may be due to the action of these drugs on inflammation, macrophage recruitment, and cholesterol efflux as well as direct effects on vascular smooth muscle and endothelial cells 21.

The aforementioned putative CV and metabolic benefits of TZDs have raised interest in TZDs as potential modulators of CV outcomes in patients with T2DM or insulin resistance. However, the use of TZDs has been hampered by their adverse effects which include weight gain (due to expansion of adipose tissue and edema), edema, heart failure (due to volume expansion, rather than direct myocardial effects), and bone fractures 21,23. There has been controversy regarding an increased risk of bladder cancer, but a recent large, 10-year study involving a cohort and case–control analysis did not confirm an increased risk of this neoplasm with pioglitazone 38.

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Early trials

Only a handful of studies have investigated the CV outcomes of T2DM treated with TZDs.

PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was a prospective randomized-controlled trial designed to investigate the possible CV benefit of pioglitazone in T2DM with known macrovascular disease 39. A total of 5238 patients were randomized to pioglitazone or placebo in addition to their current glucose-lowering drugs. After a mean follow-up of 34 months, there were no significant differences in the primary endpoint of all-cause mortality, nonfatal MI, stroke, acute coronary syndrome (ACS), vascular interventions, and above the ankle amputations. However, the study did show a significant reduction in the composite secondary endpoint of death from any cause, nonfatal MI and stroke [hazard ratio (HR)=0.84, 95% confidence interval (CI): 0.72–0.98, P=0.027]. The CV benefits of the PROactive study were counterbalanced to some extent by more frequent heart failure in the pioglitazone treated group. A subgroup analysis of PROactive assessed CV outcomes in individuals with previous MI. No differences were observed in the primary or secondary endpoints established by the main PROactive study, but a significant reduction in fatal and nonfatal MI (HR=0.72, 95% CI: 0.52–0.99, P=0.045), ACS (HR=0.63, 95% CI: 0.41–0.97, P=0.0346), and a composite cardiac endpoint of time to MI, coronary revascularization, ACS, and cardiac death (HR=0.81, 95% CI: 0.66–0.98, P=0.034) were seen 40. A recent 6-year follow-up analysis of the PROactive cohort demonstrated that the macrovascular benefits of the trial were not sustained without continued use of pioglitazone 41.

A meta-analysis of randomized, controlled trials, including the PROactive trial, supported the PROactive findings 42. Lincoff and colleagues performed an independent analysis of 19 trials enrolling 16 390 patients from a database provided by Takeda, the manufacturer of pioglitazone. They evaluated CV endpoints in diabetics on pioglitazone versus either placebo or control diabetic therapy. The primary endpoint was a composite of death from any cause, nonfatal MI, or nonfatal stroke and the secondary endpoint was serious heart failure. Compared with controls, patients treated with pioglitazone demonstrated a significant reduction in the primary endpoint (HR=0.82, 95% CI: 0.72–0.94, P=0.005). Similar to PROactive, incidence of serious heart failure was higher in the pioglitazone treated group (HR=1.41, 95% CI: 1.14–1.76, P=0.002) without associated increase in mortality. Although not discussed in detail here, several observational studies have also supported a beneficial effect of pioglitazone on cardiovascular disease (CVD) or all-cause mortality in T2DM 43–45.

The use of rosiglitazone, and consequently the TZDs in general, has been hindered by controversy surrounding its CV effects. A meta-analysis of several small studies assessing the glucose-lowering effects of rosiglitazone suggested an association of rosiglitazone with MI and an overall trend towards death from CV causes 46. This led to an Food and Drug Administration (FDA)-imposed restriction on the drug in 2010, which has subsequently been reversed. The Rosiglitazone Evaluated for CV Outcomes in Oral Agent Combination Therapy for type 2 Diabetes study was the only prospective trial to more directly assess CV outcomes in patients treated with rosiglitazone 47,48. This was a multicenter, randomized, open-label, noninferiority trial assessing CV outcomes with addition of rosiglitazone to metformin or sulfonylurea compared with the combination of metformin and a sulfonylurea in 4447 patients with T2DM. The primary endpoint was time to first CV hospitalization or death. There was no increase in the incidence of MI or CV death. However, the rate of heart failure hospitalizations was doubled in the rosiglitazone group compared with the control group, and bone fractures were increased in the TZD group (a phenomenon previously reported with both members of this class.) An FDA mandated reanalysis of the Rosiglitazone Evaluated for CV Outcomes in Oral Agent Combination Therapy for type 2 Diabetes trial later lead to similar conclusions as the original trial 49 and the FDA removed its restrictions on the drug in 2013.

Additional data on the cardiac safety of rosiglitazone came from a post-hoc analysis of the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial in patients with known CAD 50. CV events were assessed in 2368 patients with T2DM and CAD, treated with rosiglitazone or not treated with a TZD. Primary outcome was total mortality and secondary outcome composite death, MI and stroke during 4.5 years of follow-up. The investigators observed no differences in mortality nor ischemic CV events with rosiglitazone treatment.

Bypass Angioplasty Revascularization Investigation 2 Diabetes was originally designed to investigate treatment strategies for patients with diabetes and CAD 51. The study randomized patients to prompt revascularization versus medical therapy, as well as to insulin sensitization (metformin and TZDs) versus insulin provision therapy (sulfonylureas and insulin) to achieve a HbA1c less than 7.0%. The primary endpoint was death from any cause with a principal secondary composite endpoint of death, MI, or stroke. Patients in the insulin-sensitization group had lower HbA1c levels throughout the follow-up period but no differences were seen in either primary or secondary endpoints between the insulin sensitization and insulin provision groups at 5 years. Peripheral edema was more frequent in the insulin-sensitization group but the rate of heart failure did not differ. There was an interesting subgroup finding that individuals randomized to prompt revascularization who were also assigned to the insulin-sensitization group experienced ∼19% fewer major adverse CV events than those assigned to insulin provision, but this result did not quite achieve statistical significance (20.3 vs. 25.2%, P=0.059.) This effect was predominately driven by those who received coronary artery bypass grafting (18.7 vs. 26.09%, P=0.066) 51. This analysis suggests the possibility that the combined approach of coronary revascularization and insulin sensitizer therapy might be most efficacious in patients with CAD and T2DM.

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Insulin Resistance Intervention after Stroke

Despite current preventive and treatment efforts, stroke continues to be a major cause of mortality and morbidity worldwide. Approximately 795 000 people have a new (610 000) or recurrent stroke (185 000) yearly in the USA and about 130 000 people die primarily from this disease. It is projected that by 2030, an additional 3.4 million adults will have had a stroke 1. There is a high risk of stroke recurrence, as well as of MI, in individuals who have already had a stroke, making both primary and secondary prevention essential. Currently, the major recommendation for secondary prevention is antiplatelet therapy and risk factor reduction, including blood pressure control, treatment of dyslipidemia with statins, diabetes control, smoking cessation and weight loss 52. In selected circumstances of significant carotid obstruction, carotid revascularization is also indicated. In the setting of cardioembolic stroke, most typically from atrial fibrillation, systemic anticoagulation is advised unless specific contraindications prevail.

In addition to traditional risk factors, insulin resistance is now recognized as a risk factor for stroke. It has been found to be associated with a 60–160% increased risk of stroke in nondiabetic patients and 50% of nondiabetic patients with a recent transient ischemic attack (TIA) or ischemic stroke were found to be insulin resistant 53. Pioglitazone has been shown to improve insulin sensitivity in insulin resistant nondiabetic individuals with recent TIA or stroke in a small randomized, double-blind, placebo-controlled study. Improved insulin sensitivity was demonstrated with pioglitazone treatment at 3 months (62% increase with pioglitazone vs. 1% decline with placebo, P=0.0006) 54.

Emerging data indicate that therapy directed at insulin resistance may improve CV outcomes in patients after stroke. In a subgroup analysis of the PROactive study T2DM patients with previous stroke demonstrated a dramatic reduction in fatal or nonfatal stroke in patients treated with pioglitazone compared with placebo with event rates of 5.6 versus 10.2% respectively (HR=0.53, 95% CI: 0.34–0.85, P=0.0085) 55. CV death, nonfatal MI, or nonfatal stroke was also reduced in the pioglitazone group with an event rate of 13.0 versus 17.7% with placebo (HR=0.72, 95% CI: 0.52–1.00, P=0.0467).

In patients with T2DM, the benefit of pioglitazone could be attributed to both glucose-lowering and the pleiotropic effects of the drug. Whether pioglitazone could reduce the risk of subsequent CV events in a stroke population without diabetes remained unknown. In this context, the Insulin Resistance Intervention after Stroke (IRIS) trial investigators hypothesized that pioglitazone would reduce rates of stroke and MI following ischemic stroke or TIA in nondiabetic individuals with insulin resistance 56,57. The IRIS investigators postulated that treating insulin resistance before the development of overt hyperglycemia could potentially have an impact on reducing CV events.

The IRIS study was an international, multicenter, double-blind, randomized, placebo-controlled trial in which 3876 patients with insulin resistance and a recent stroke or TIA were randomized to pioglitazone or placebo. Insulin resistance was defined as a homeostasis model assessment of insulin resistance more than 3.0. This equation is simply derived from fasting plasma glucose and insulin concentrations. The primary outcome was fatal or nonfatal stroke or MI and secondary outcomes were fatal or nonfatal stroke, ACS (MI or unstable angina), onset of diabetes, cognitive decline, stroke, MI, hospitalization for heart failure, and all-cause mortality. The study showed a significant reduction in the primary outcome with patients assigned to the pioglitazone group 24% less likely to have a stroke or MI at 5 years compared with the placebo group (HR=0.76, 95% CI: 0.62–0.93, P=0.007). Other outcomes are shown in Table 1.

Table 1

Table 1

Consistent with previous studies 26, patients treated with pioglitazone in IRIS had significantly less risk of developing new onset diabetes (3.8% in pioglitazone group vs. 7.7% in the placebo group, HR=0.48, 95% CI: 0.33–0.69, P<0.001). Patients treated with pioglitazone also had lower fasting glucose, insulin levels (and, as a result homeostasis model assessment of insulin resistance), lower triglycerides, higher fasting high-density lipoprotein, as well as lower systolic and diastolic blood pressures (up to the 4 year mark).

The IRIS study participants randomized to pioglitazone did show significant increases in weight, edema, and bone fractures. These were known deleterious effects of the drug 21,23. Bone fractures requiring surgery or hospitalization occurred in 5.1% of those randomized to pioglitazone and 3.2% randomized to placebo (P=0.003). No statistically significant differences in the development of bladder cancer were observed (0.6 vs. 0.4% in the pioglitazone vs. placebo groups, P=0.37) and there was no overall difference in incidence of all cancers (6.9 vs. 7.7%, P=0.29). Importantly, there was no significant difference in the development of heart failure with pioglitazone therapy. This may be because IRIS excluded patients with pre-existing heart failure and also allowed for the use of reduced doses of pioglitazone in patients who developed new or worsening edema, shortness of breath, myalgias or excessive weight gain. The median daily dose of pioglitazone each year ranged between 29 and 40 mg.

In parallel with IRIS, the smaller J-SPIRIT study also evaluated the effect of pioglitazone on recurrent stroke in patients with impaired glucose tolerance and newly diagnosed diabetes 58. This prospective, open-label study randomized half of its 120 patients with a history of ischemic stroke or TIA and impaired glucose tolerance or newly diagnosed diabetes to pioglitazone. The majority of the patients (about 2/3) were treated with a 15 mg dose and the remainder with a 30 mg daily dose. During a median follow-up of 2.8 years, the pioglitazone treated group had a lower rate of recurrent stroke but the difference was not statistically significant (4.8% event rate in pioglitazone group vs. 10.5% in control group, HR=0.62, 95% CI: 0.13–2.35, P=0.49). This result reflected an underpowered study.

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Discussion

There are now two randomized-controlled trials showing benefit in CV outcomes in patients treated with pioglitazone, one in patients with diabetes (PROactive) and one in patients with insulin resistance (IRIS). The question now arises as to whether these findings should or will alter clinical practice. Use of rosiglitazone steadily declined from a peak in 2006 to rare use following the controversy surrounding CV concerns as discussed above. Pioglitazone use reached a peak in 2008 but experienced a steep decline after 2011 around the time that rosiglitazone use was restricted by the FDA and a 5-year interim report on the risk of bladder cancer was published 59,60. Since then, despite data refuting the aforementioned risks, practitioners have, in general, shied away from using pioglitazone, also because of well-known potential adverse effects, especially weight gain, heart failure and edema, and also the availability of other, often better tolerated, glucose-lowering medications. Given its efficacy and durability in glycemic control, low cost and possible CV benefit, pioglitazone should probably now be considered more frequently in carefully selected patients with T2DM. It should be emphasized that PROactive and IRIS showed benefits in patients with known macrovascular disease, whereas the CV outcomes of pioglitazone in patients without known overt CVD remains unclear. The IRIS trial also raises the question of whether pioglitazone should be considered as secondary prevention therapy in nondiabetic patients with recent TIA or stroke. Most patients in the IRIS trial were already on what would be considered optimized secondary prevention therapy in stroke patients: blood pressure control, statin and antiplatelet therapy. All patients after TIA or ischemic stroke should be on optimal standard secondary prevention therapies, but the IRIS results therefore suggest that even these patients with insulin resistance could have their residual risk decreased further with pioglitazone.

The benefit on CV outcomes must, of course, be judiciously evaluated in the context of potential side effects. The IRIS study estimated that administration of pioglitazone to 100 patients for 5 years would prevent three patients from having an MI or stroke but would potentially result in a bone fracture requiring hospitalization or surgery in two patients. This finding suggests that pioglitazone should be avoided in patients at risk for osteoporosis and fractures.

Because of the risk for fluid retention, pioglitazone should be avoided in patients with previously diagnosed heart failure. Even in the setting of preserved systolic left ventricular function, fluid retention can precipitate heart failure with worsening symptoms. IRIS did not show an increase in heart failure with pioglitazone, but monitoring was close and the dose could be adjusted if significant edema or weight gain occurred. Such a strategy would need to be replicated to ensure patient safety. The IRIS trial also adopted a strategy that patients who develop new heart failure on therapy should be removed from pioglitazone, rather than treating them with diuretic and continuing drug. This conservative approach also likely improved the safety of pioglitazone. Whether a lower drug dose might retain efficacy but also reduce the risk of heart failure, edema, weight gain or bone fracture is unclear. Our recommendations for the safe use of pioglitazone, incorporating sound clinical judgement, are outlined in Table 2.

Table 2

Table 2

The IRIS trial should rekindle interest in pioglitazone, as well as research into other approaches to modulate insulin resistance. One trial, TOSCA.IT (NCT00700856) is currently comparing pioglitazone versus sulfonylureas as add-on therapy to metformin for patients with T2DM in terms of glycemic control, safety and CV outcomes. This study will hopefully add to our understanding of TZDs and their impact on CV outcomes. Whether other strategies to reduce insulin resistance will have a benefit on macrovascular outcomes is speculative. Indeed, it remains unknown whether pioglitazone’s benefits in IRIS were the direct result of improving insulin sensitivity or other direct or indirect vascular effects due to PPARγ activation. Development of PPARγ modulators that minimize effects in off target tissues, especially bone, while maximizing benefits on insulin resistance and atherosclerosis will be of particular interest. Finally, research into mechanisms of insulin resistance may identify novel therapeutic targets with potential clinical implications in the prevention of CVD 21–23,62,63.

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Acknowledgements

The study was funded by NIH T32DK07058 (A.L.P.), NINDS U01NS044876 (L.H.Y., S.E.I.).

Author contributions: A.L.P., L.H.Y., and S.E.I. reviewed the data and wrote the manuscript.

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Conflicts of interest

Dr Inzucchi has served as a research consultant or advisor to Merck, Boehringer Ingelheim, Novo Nordisk, Janssen, Sanofi and Astra Zeneca. He is an investigator on the IRIS trial and has taken part in research with nonfinancial support (study drug) from Takeda. Dr Young is an investigator on the IRIS trial, which is supported by the NINDS and received study drug from Takeda. For the remaining author there are no conflicts of interest.

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Keywords:

cardiovascular disease; diabetes; insulin resistance; Insulin Resistance Intervention after Stroke; pioglitazone; stroke; thiazolidinedione

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