Pioglitazone: The forgotten,cost-effective cardioprotective drug for type 2 diabetes

Abstract

Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.

Keywords

Pioglitazone type 2 diabetes mellitus cardiovascular disease

Background

Type 2 diabetes mellitus (T2DM) is a cardiometabolic disease^1,2 that affects both the microvasculature (retinopathy, nephropathy, neuropathy) and macrovasculature [myocardial infarction (MI), stroke]. The microvascular complications primarily are related to the level of glycaemic control,^3,4 whereas hyperglycaemia is a relatively weak risk factor for the macrovascular complications^3,5 which represent the major cause of mortality in T2DM patients.^6,7 Long-term cardiovascular (CV) outcome trials have generally demonstrated no or only slight reduction in CV events with intensive glycaemic control.^3,8–10 In contrast, treatment of more traditional CV risk factors (blood pressure, dyslipidaemia) consistently has been associated with major CV benefits in T2DM patients.¹

The results of recent CV outcome trials have documented that glucose-lowering agents in two different classes significantly reduce the MACE (major adverse cardiovascular events) endpoint (composite of CV mortality, non-fatal MI, non-fatal stroke). In both the EMPA REG OUTCOME trial¹¹ and in the CANVAS program,¹² the sodium glucose transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, reduced MACE by 14% and 13%, respectively, although the relative contributions of the three individual components of the composite outcome differed. In LEADER¹³ and SUSTAIN-6,¹⁴ therapy with the glucagon-like-peptide receptor agonists (GLP-1 RAs), liraglutide and semaglutide, resulted in reductions in MACE of 13% and 26%, respectively, and also with differential contributions from the composite elements. Importantly, empagliflozin and liraglutide were each associated with significant reductions in CV mortality as well. With the robust results of these large, long-term, CV outcome trials, we are entering a new era of T2DM treatment where glucose-lowering drugs that address both glycaemia, as well as CV risk, are now preferred in patients with cardiovascular disease (CVD) over those therapies that simply lower HbA1c.¹⁵

In the midst of the newfound interest in the SGLT2 inhibitors and GLP-1 RAs, the established anti-atherogenic benefits of the thiazolidinedione (TZD), pioglitazone, have been overlooked.¹⁶ The recent results of the IRIS (Insulin Resistance Intervention after Stroke) trial¹⁷ should rekindle interest in pioglitazone as a cardioprotective drug, an effect which actually was established more than a decade ago. Because pioglitazone is now generically available, it represents a more affordable option than either an SGLT2 inhibitor or a GLP-1 RA.¹⁸ Furthermore, it can be combined with these and other glucose-lowering agents, including the SGLT2 inhibitors or GLP-1 RAs, to minimize side effects.^15,18–20 Pioglitazone also has a number of other demonstrated benefits, including amelioration of insulin resistance, preservation of beta-cell function, durable glycaemic control, improvement of multiple factors of the metabolic syndrome and reversal of hepatic steatosis [nonalcoholic fatty liver disease (NAFLD)]/nonalcoholic steatohepatitis (NASH) making it an attractive option for the treatment of many patients with T2DM, particularly those at risk for CV events. In this review, we examine the CV, glycaemic and other metabolic benefits of pioglitazone and provide strategies to maximize the drug’s benefit: risk ratio.

CV benefit

A substantial body of evidence, including large randomized prospective CV outcome trials,^{16,17,21–23} real-world observational studies^24–26 and smaller studies of regression of coronary atherosclerosis²⁷ and carotid intima thickness,²⁸ has demonstrated that pioglitazone reduces both atheroma progression and related CV events. These investigations were initiated because of a substantial literature dating back many decades that has linked insulin resistance to premature coronary heart disease (CHD).²⁹ These data begged the question as to whether reducing insulin resistance with an insulin-sensitizing drug would provide a CV benefit. The question is also of historical importance, since the notion that a diabetes drug could reduce CV events had eluded investigators for years. In PROactive, 5238 T2DM patients with a prior CV event were randomized to pioglitazone or placebo and followed for a mean of 2.9 years.¹⁶ Although the primary endpoint, a broad composite that included leg revascularization procedures, fell short of statistical significance [hazard ratio (HR) = 0.90, p = 0.09], the ‘main secondary endpoint’, MACE, was significantly reduced (HR = 0.84, p = 0.027) (Figure 1), on par with the effect size in the aforementioned recent positive trials of newer glucose-lowering agents.^11–15 In PROactive participants with a prior MI (n = 2445) or prior stroke (n = 948) pioglitazone therapy were associated with robust 28% and 47% reductions in recurrent MI³⁰ and recurrent stroke,³¹ respectively. The primary endpoint in PROactive¹⁶ should be interpreted in the context that leg revascularization historically has not been included as an endpoint in CV outcome trials since it is refractory to antihypertensive, lipid-lowering and glucose-lowering therapy.^32,33 Consistent with PROactive, a meta-analysis of published pioglitazone studies and reported to the Food and Drug Administration (FDA) demonstrated a 25% reduction in CV events.^21,22

Figure 1.

(a) Kaplan–Meier plot of time to MACE endpoint (cardiovascular mortality, non-fatal MI, non-fatal stroke) in T2DM patients treated with pioglitazone (PIO) or placebo (Plc) in PROactive. Redrawn with permission from Dormandy et al.¹⁶ (b) Pioglitazone reduces recurrent MI in diabetic patients with a previous MI in PROactive. Redrawn with permission from Erdmann et al.³⁰ (c) Pioglitazone reduces recurrent stroke in diabetic patients with a previous stroke in PROactive. Redrawn with permission from Wilcox et al.³¹ (d) Meta-analysis of all published studies (excluding PROactive) in which the effect of pioglitazone versus placebo or active comparator on cardiovascular events is examined. Redrawn with permission from Lincoff et al.²¹

Based upon (1) evidence that insulin resistance was a strong risk factor for stroke as well CHD,² (2) the consistently positive results observed in these CV outcome trials,^{16,17,21,22,24–28} and (3) the reduction in recurrent stroke (by 47%) and MI (by 28%) in T2DM individuals in PROactive,¹⁶ the National Institutes of Health initiated the IRIS study.¹⁷ In 3876 non-diabetic, insulin-resistant individuals with a recent transient ischaemic attack (TIA) or stroke, pioglitazone reduced fatal/non-fatal stroke or MI by 24% (p = 0.007) over a mean of 4.8 years (Figure 2).¹⁷ In a follow-up report from this study,³⁴ pioglitazone reduced the risk of any stroke by 25% (p = 0.01) and decreased the risk of acute coronary syndrome by 29% (p = 0.02), with most of the drug’s effects on type 1 MIs (HR = 0.62, p = 0.03), particularly large infarcts (HR = 0.44, p = 0.02).³⁵ These results compare favourably with results obtained with aspirin and anti-platelet drugs,^36–38 as well as with statins,³⁹ which are now widely used for stroke prevention.^36–38 Notably, the positive beneficial CV effects of pioglitazone in all of these studies occurred on the background of widespread use of evidence-based CV therapies including anti-platelet agents suggesting that pioglitazone can effectively address ‘residual CV risk’.

Figure 2.

Effect of pioglitazone versus placebo on recurrent stroke and myocardial infarction in the Insulin Resistance Intervention after Stroke (IRIS) study. Drawn from the data in Kernan et al.¹⁷

Observational ‘real-world’ data also support the CV benefits of pioglitazone. For example, a retrospective analysis of 91,511 patients in the UK Research General Practice Database (GPRD) who were followed for 7.1 years demonstrated that pioglitazone decreased all-cause mortality by 39% compared with metformin.⁴⁰ In a separate analysis of 27,457 GPRD patients who had a second agent added to metformin monotherapy, pioglitazone therapy was associated with a significantly decreased HR for all-cause mortality (HR = 0.71) and the combined endpoint of all-cause mortality/major adverse CV events (HR = 0.75).²⁴ In a more recent observational study,²⁵ pioglitazone significantly reduced both CV (HR = 0.58) and non-CV (HR = 0.63) mortality in a large (n = 62,266) European cohort of diabetic patients. In a study which compared 56,536 patients with T2DM who were first-time users of pioglitazone or insulin, propensity scores showed a 67% reduction in all-cause mortality in favour of pioglitazone.²⁶ In a meta-analysis of nine randomized controlled trials, pioglitazone significantly reduced the risk of major CV events in patients with diabetes [HR = 0.83, 95% confidence interval (CI) = 0.72–0.97] and prediabetes or insulin resistance (HR = 0.77, 95% CI = 0.64–0.93).⁴¹ The results of this meta-analysis are consistent with a previous one by Lincoff et al.²¹ Finally, consistent with the IRIS study, another retrospective study from the UK using Clinical Practice Research Datalink (CPRD) found a HR of 0.63 for incident stroke in T2DM patients who were users of pioglitazone versus other glucose-lowering drugs.⁴²

Smaller mechanistic studies are consistent with the findings from these large prospective and observational studies and meta-analyses. In the PERISCOPE study, pioglitazone, compared with glimepiride, retarded the progression of coronary atherosclerosis as measured by intravascular ultrasound (IVUS),²⁷ while in the CHICAGO study, pioglitazone slowed the rate of increase in carotid intimal thickness, a surrogate measure of atherosclerosis.²⁸ Pioglitazone has been shown to reduce intracoronary plaque volume in non-diabetic⁴³ and type 2 diabetic⁴⁴ subjects and to prevent restenosis after stent placement.⁴⁵

One negative pioglitazone study to consider is the recent CV outcome trial from Italy, TOSCA-IT.⁴⁶ A total of 3041 T2DM patients with suboptimal glycaemic control on metformin monotherapy were randomized to either pioglitazone or a sulphonylurea and followed for a mean of 4.8 years. Because only 11% had a prior history of CVD, this was essentially a primary prevention population. The primary outcome (all-cause death, non-fatal MI, non-fatal stroke and urgent coronary revascularization) occurred at a similar frequency between the two groups: pioglitazone 6.8% versus sulphonylurea 7.2% (HR = 0.96, p = 0.40). Unfortunately, the study had some methodological limitations, including its unblinded design and the fact that many patients in the pioglitazone arm had either terminated their participation early (10%) or had stopped the study drug (28%), likely stemming from controversy about the drug’s safety that had arisen during the trial. Furthermore, the CV event rate, 1.5 per 100 person years, was very low, rendering the study greatly underpowered to detect any effective CV events. This issue was underscored by an a posteriori per-protocol analysis focusing on just those patients taking their study drug. Here, a secondary outcome that included peripheral vascular events was significantly reduced by study drug (HR = 0.67, p = 0.03). Of course, this outcome must be interpreted cautiously.

In summary, a large body of evidence from clinical trials to observational studies to mechanistic investigations document that pioglitazone effectively prevents recurrent CV events in both diabetic and non-diabetic individuals, most likely through a beneficial effect on atherosclerosis. The only negative study to our knowledge, TOSCA-IT, involved patients generally without CVD and had multiple interpretative challenges.

Appropriate concern has been raised about ‘heart failure’ (HF) in PROactive. Due to increased renal sodium retention, all TZDs are associated with oedema,⁴⁷ which is a nonspecific sign of HF by clinicians. Since the HF cases in PROactive were not adjudicated, it remains possible that at least some of the excess events may have reflected cases of oedema without cardiac decompensation. HF is typically an ominous diagnosis in patients with diabetes, with a 5-year mortality in excess of 50%.^1,45 Given that mortality in this cohort of individuals with HF in PROactive was decreased (not increased), albeit not significantly, it is possible even likely that not all (probably many) patients diagnosed with HF actually had HF. In fact, in smaller trials, pioglitazone has been demonstrated to have no deleterious effect on left ventricular (LV) function,^48,49 to actually improve diastolic dysfunction,^48–50 to reduce blood pressure,^48,49 and to increase myocardial insulin sensitivity.^48,49 Interestingly, prior to the concern about HF, observational data suggested that this drug class might actually decrease mortality after HF admissions.¹⁶ Thus, participants in PROactive who were diagnosed with HF did not experience any increase in CV events compared to placebo-treated individuals.¹⁶ In IRIS, HF was not increased, although this cohort of cerebrovascular patients had less CHD than did participants in PROactive.^17,51 Also, the IRIS protocol allowed for dose reductions in the setting of significant weight gain or oedema. These observations are consistent with previous findings that pioglitazone improves diastolic function in diabetic rats⁵² and humans^48,53 by positively influencing matrix remodelling.^52,53 A recent meta-analysis suggests that pioglitazone also reduces both new onset and recurrent atrial fibrillation by 27%.⁵⁴

Metabolic effects of pioglitazone

The insulin resistance syndrome (IRS), originally referred to as the metabolic syndrome, comprises a cluster of cardiometabolic disorders, each representing an independent CV risk factor.² Pioglitazone improves each component of the IRS (Table 1) (reviewed in previous studies^2,55–58). It enhances insulin sensitivity and effectively reduces plasma glucose levels and HbA1c while also lowering blood pressure and having a favourable effect on the plasma lipid profile. The latter includes a reduction in triglycerides and free fatty acids (FFAs), increase in high-density lipoprotein (HDL) cholesterol and conversion of small dense low-density lipoprotein (LDL) particles to larger, more buoyant, less atherogenic ones. The drug also shifts fat from visceral abdominal depots, from liver and from skeletal muscle to subcutaneous abdominal depots,^59–62 thereby ameliorating lipotoxicity.^2,55,63–66 It normalizes adipocytokine secretion, especially adiponectin, improves endothelial dysfunction and reduces circulating concentrations of the procoagulant plasminogen activator inhibitor-1 and the pro-inflammatory mediator C-reactive protein (CRP).^66,67 Although pioglitazone improves multiple CV risk factors, both preclinical^68–70 and clinical^{16,17,21–23,27,28,71}, data suggest that pioglitazone exerts direct anti-atherogenic effects on the arterial wall.

Table 1.

Effect of pioglitazone on established CV risk factors.

CV risk factors	Effect of pioglitazone
Obesity (visceral)	Improves – redistributes fat^a
Hypertension	Decreases BP
Hypertriglyceridaemia	Decreases TG
Low HDL cholesterol	Increases HDL
Small dense LDL particles	Converts to larger more buoyant LDL
Endothelial dysfunction	Improves
Hyperglycaemia	Durable decrease in HA1c
Inflammation (hsCRP)	Reduces
Lipotoxicity	Reverses
NASH/NAFLD	Improves
PAI-1	Reduces
Hyperinsulinaemia	Decreases
Insulin resistance	Improves

CV: cardiovascular; BP: blood pressure; TG: triglyceride; HDL: high-density lipoprotein; LDL: low-density lipoprotein; hsCRP: high-sensitive C-reactive protein; NASH/NAFLD: nonalcoholic steatohepatitis/nonalcoholic fatty liver disease.

Although subjects treated with pioglitazone may gain weight, visceral, hepatic and muscle fat content are decreased.

Pioglitazone transacts its effects through activation of the nuclear hormone receptor peroxisome proliferator–activated receptor-gamma (PPARγ).⁷² PPARγ receptors are expressed in endothelial cells, arterial smooth muscle cells and monocytes/macrophages, providing a pathway for direct anti-inflammatory, antioxidant and other protective actions of pioglitazone.^73–77 Pioglitazone is the only true insulin-sensitizing antidiabetic agent⁷⁸ and insulin resistance has been independently associated with atherosclerotic CVD in many cross-sectional and prospective studies.^{2,29,58,79–84}

Pioglitazone is a potent insulin sensitizer

The core pathophysiologic defects in T2DM are insulin resistance in muscle and liver and beta-cell failure.^2,55,85 Collectively, these three pathophysiologic disturbances have been termed the TRIUMVIRATE.^2,55 Insulin resistance in liver results in excess glucose production during the sleeping hours and is the primary factor responsible for fasting hyperglycaemia, while insulin resistance in muscle is the primary factor responsible for postprandial hyperglycaemia. Impaired suppression of hepatic glucose production and reduced liver glucose uptake following a meal also contribute to the postprandial hyperglycaemia.^55,85 Progressive beta-cell failure^55,85–88 accentuates the insulin resistance in liver and muscle. In addition, the adipocyte is resistant to insulin,^2,55,85 resulting in accelerated lipolysis and increased circulating plasma FFA concentrations.^89,90 Elevated plasma FFA in turn exacerbate the muscle insulin resistance,⁹¹ stimulate hepatic gluconeogenesis and inhibit hepatic glucose uptake⁹² and impair beta-cell function.⁹³ Pioglitazone improves insulin sensitivity in skeletal^{2,55,72,94–96} and cardiac^48,49 muscle, in liver⁹⁷ and in adipose tissue⁹⁸ via multiple mechanisms: PPARγ activation, stimulation of the insulin signal transduction system, improved glucose transport/glycogen synthesis/glucose oxidation, increased mitochondrial function, reduced plasma FFA levels and reversal of lipotoxicity.^2,55,63–66

Pioglitazone improves beta-cell function

Insulin resistance is the earliest detectable disturbance in the natural history of T2DM.^2,55,85 However, overt diabetes does not develop in the absence of beta-cell failure and progressive decline in insulin secretion.^2,55,85–88 Although not well appreciated, TZDs, including pioglitazone, in addition to their insulin-sensitizing action, exert a potent effect to preserve beta-cell function^99,100 and durability of glycaemic control has been demonstrated in eight long-term, double-blind, placebo-controlled or active comparator studies for up to 5 years (reviewed by DeFronzo⁵⁵). Multiple studies performed in subjects with impaired glucose tolerance (IGT) also have demonstrated a potent action of TZDs to augment beta-cell function (reviewed in previous studies^86,100,101). For example, in the ACT NOW study,^100,102 conversion of IGT to T2DM was reduced by 72% and improvement in the insulin secretion/insulin resistance (disposition) index (gold standard measure of beta-cell function) was the strongest predictor of diabetes prevention.¹⁰⁰ The improvement in beta-cell function is related to stimulation of PPARγ receptors on the beta cell, enhanced beta-cell sensitivity to glucose and reversal of lipotoxicity.^55,103

Pioglitazone improves NASH/NAFLD

NAFLD has reached epidemic proportions in the United States and worldwide¹⁰⁴ and is the precursor for NASH.¹⁰⁵ Diabetic patients with NASH are at high risk for cirrhosis and hepatocellular carcinoma.¹⁰⁶ Patients with NAFLD/NASH are markedly resistant to insulin, often have the metabolic syndrome and are also at increased risk for CVD.^107–110 Because pioglitazone improves insulin sensitivity, corrects multiple components of the IRS, ameliorates lipotoxicity and protects against atherosclerotic CVD, it would be an excellent agent for the treatment of NAFLD and NASH. Indeed, multiple studies have demonstrated that pioglitazone consistently reduces hepatic fat content and reverses hepatic fibrosis.^59–62 No other antidiabetic agent other than rosiglitazone, a TZD, has shown benefit in the treatment of NAFLD/NASH.^111,112

Safety concerns

Fat weight gain

Weight gain is common with pioglitazone therapy, typically amounts to ~2 to 3 kg of fat mass over 1 year^16,113,114, and is dose related.^113,115 Of note, the greater is the weight gain, the greater is the decline in HbA1c and the greater are the improvements in insulin secretion and insulin sensitivity.^94,99,116 How is this explained? Pioglitazone causes an increase in body weight by stimulating PPARγ receptors in the hypothalamus to augment appetite.¹¹⁷ However, pioglitazone simultaneously stimulates PPARγ receptors in subcutaneous adipocytes to induce genes involved in adipogenesis.¹¹⁸ The newly formed, smaller fat cells take up FFA leading to a reduction in the plasma FFA concentration and decreased flux of FFA into liver, muscle and visceral fat depots. In addition, pioglitazone stimulates PPARγ coactivator-1 (PGC-1) which is the master switch for mitochondrial biogenesis.^119,120 This causes transcription of mitochondrial genes involved in fatty acid oxidation, resulting in a further reduction in the intramyocellular and hepatocyte lipid content with reversal of lipotoxicity.^2,55,121 It is noteworthy that weight gain, not weight loss, was associated with increased survival in the PROactive study.¹²² This observation suggests that pioglitazone also mobilizes fat out of the arterial wall (see preceding discussion).

It is notable that no specific adverse effects of the fat weight gain have been observed in T2DM patients treated with pioglitazone for up to 3–6 years.^{16,17,23,62,123} Importantly, the weight gain is dose related and can be minimized by not exceeding a dose of 30 mg/day,¹¹³ the point at which ~80% of the drug’s glucose-lowering efficacy is observed. Combination therapy of pioglitazone with metformin minimizes the weight gain,¹²⁴ while combination therapy with a SGLT2 inhibitor^19,20 or with a GLP-1 RA^19,125,126 reduces both the weight gain and fluid retention.

Fluid retention and HF

When used as monotherapy, oedema is observed in 5%–10% of pioglitazone-treated individuals and, like weight gain, is dose related.^113,115 When used in combination with a sulphonylurea or insulin, the incidence of oedema is increased further.¹¹⁵ The oedema results from two factors: peripheral vasodilation¹²⁷ and renal sodium retention.¹²⁸ Despite increased total body sodium, blood pressure consistently declines,^48,49,56 indicating that the drug’s predominant effect is on the vasculature to decreased vascular tone, and that sodium retention is secondary to the vasodilation. Pioglitazone has no apparent negative effect on LV function^48,49 and improves diastolic dysfunction.^48–52 Nonetheless, pioglitazone should not be used in T2DM patients with symptomatic HF since fluid accumulation in a noncompliant ventricle can precipitate HF in such individuals, leading to clinical deterioration.¹¹⁵ Salt and water retention respond best to diuretics that act in the distal tubule such as spironolactone, triamterene and amiloride.¹¹⁵ Patients should be instructed to report new oedema or dyspnoea to their physician. If more than trace oedema is present, treatment with one of the distally acting diuretics should be instituted and/or the dose of pioglitazone reduced. Of note, in the IRIS study,¹⁷ the number of patients who developed HF was similar in the pioglitazone-treated (n = 74) and placebo-treated (n = 71) groups and this study did allow for dose reduction for oedema or weight gain not responding to initial lifestyle recommendations.

Bone fractures

An increase in bone fractures has been reported in T2DM individuals treated with TZDs.^17,129–132 The fractures primarily affect postmenopausal women, occur in the distal long bones of the hands and feet and are related to trauma. One study has reported an increase in fractures in men,¹⁷ while some studies have failed to observe any increase in fractures in either sex.⁴⁶ The excess fracture risk amounts to 0.8 fractures per 100 patient-treatment years (1.9 vs 1.1 in pioglitazone vs comparator-treated group).^129–132 Fractures are uncommon in premenopausal women and men. Pioglitazone should be used cautiously or not at all in individuals at high fracture risk, including postmenopausal women with osteoporosis or those with prior fracture.

Bladder and cancer

In PROactive,¹⁶ there was a nonsignificant increase in the number (16 vs 6, p = 0.069) of patients who developed bladder cancer. Before unblinding of the results, external experts adjudicated that 11 cases could not plausibly be related to treatment (due to the temporal sequence of drug exposure and cancer diagnosis), leaving six cases in the pioglitazone group and three cases in the placebo group (p = 0.309). Of note, there were significantly fewer cases of breast cancer (3 vs 11, p = 0.034) in the pioglitazone-treated group and the overall incidence of cancer was similar in both groups. Also, after 10 years of follow-up, the incidence of bladder cancer was similar in pioglitazone-treated versus placebo-treated subjects (28 vs 26, respectively).²³ After PROactive, the FDA requested that the manufacturer of pioglitazone initiates a prospective study to examine the relationship between pioglitazone and bladder cancer. A midpoint analysis of this 10-year study¹³³ involving 193,099 patients revealed no significant association between pioglitazone and bladder cancer (HR = 1.2, 95% CI = 0.9–1.5, p = NS), but those who were exposed for at least 2 years had a small increased risk (HR = 1.4, 95% CI = 1.0–2.0). The 10-year follow-up data, however, failed to find any such association between pioglitazone and bladder cancer with sensitivity analyses showing that the neutral effect was present irrespective of dose and duration of therapy (HR = 1.06, 95% CI = 0.89–1.26, p = NS).¹³⁴ In a multinational cohort¹³⁵ involving 1.01 million T2DM patients with greater than 5.9 million person-years, the HR for bladder cancer with pioglitazone and rosiglitazone was 1.01 and 1.00, respectively (both p = NS). In the recently published IRIS study,¹⁷ no increase in bladder cancer was observed in the pioglitazone group (0.6% vs 0.4%, p = 0.37). Based upon the preceding body of evidence, however, the FDA still cautions about this risk and recommends that pioglitazone not be used in diabetic patients with active bladder cancer or history of bladder cancer.

Summary

As we transition to a new evidence-based era of T2DM management in patients with CVD,¹⁵ it is imperative that we choose therapies that not only improve glycaemic control but also improve CV outcomes–the latter representing the greatest cause of mortality in this population. Pioglitazone has been shown to reduce MACE (MI, stroke and CV mortality) in multiple studies including PROactive,¹⁶ IRIS,¹⁷ meta-analyses of multiple prospective studies;^21,22 to reduce CV events and mortality in several large observational studies;^24–26,40 to retard the anatomical progression of coronary and carotid atherosclerosis in PERISCOPE,²⁷ Chicago²⁸ and ACT NOW (Table 2).¹⁰² Pioglitazone is the only available insulin-sensitizing agent and has a potent beneficial effect to improve and preserve beta-cell function, leading to a durable reduction in HbA1c (Table 2). Pioglitazone also corrects multiple components of the metabolic syndrome and is an effective treatment for NASH/NAFLD. Side effects remain a concern but can be mitigated by optimizing dosing strategies and combining therapy with other medications (metformin, SGLT2i, GLP-1 RA) that promote weight loss and sodium excretion. The benefit to risk ratio of pioglitazone is very favourable when caution is employed to avoid the known side effects of the drug (Table 2). Moreover, pioglitazone is now generically available and some 50 times less expensive than many branded glucose-lowering drugs with recent CV benefits. It, therefore, represents a highly affordable option for the treatment of patients with T2DM, especially those with prevalent CVD.

Table 2.

Benefits and risk associated with pioglitazone therapy.

Benefit	Risk
Potent, durable HbA1c reduction	Fat weight gain – but decreases visceral, hepatic and muscle fat content
Low risk of hypoglycaemia	Fluid retention/heart failure
Improves insulin resistance	Bone fractures (distal long bones, trauma related)
Improves beta-cell function	Bladder cancer (not established)
Prevents IGT progression to T2DM
Improves cardiovascular risk factors (HDL, triglyceride, blood pressure, inflammation)
Reduces microalbuminuria
Decreases cardiovascular events in high-risk diabetic patients (PROactive, IRIS, meta-analysis)
Reduces cardiovascular events in diabetic patients with chronic kidney disease
Improves endothelial dysfunction
Improves NASH/NAFLD

IGT: impaired glucose tolerance; T2DM: type 2 diabetes mellitus; HDL: high-density lipoprotein; NASH/NAFLD: nonalcoholic steatohepatitis/nonalcoholic fatty liver disease.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.A.D. serves the Advisory Board of AstraZeneca, Novo Nordisk, Janssen, Boehringer Ingelheim, Intarcia and Elcelyx; research support in Boehringer Ingelheim, Takeda, AstraZeneca and Janssen; speaker’s bureau in Novo Nordisk, AstraZeneca and Merck. S.I. serves the Clinical trial Steering/Executive Committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk and Eisai (TIMI); data monitoring committees for Intarcia; consultant for Janssen and vTv Therapeutics. M.A-G. has no conflict of interest with this manuscript. S.E.N. reports that the Cleveland Clinic centre for Clinical Research has received funding to perform clinical trials from AbbVie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Pfizer, The Medicines Company, Takeda and Orexigen. He is involved in these clinical trials, but receives no personal remuneration for his participation; consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Ralph A DeFronzo

References

Low Wang

Hess

Hiatt

et al . Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus – mechanisms, management, and clinical considerations. Circulation 2016; 133: 2459–2502.

DeFronzo

RA.

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links: the Claude Bernard Lecture 2009. Diabetologia 2010; 53: 1270–1287.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.

Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 1993; 329: 977–986.

Stratton

Adler

Neil

et al . Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–412.

Morrish

Wang

Stevens

et al . Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001; 44: S14–S21.

Rawshani

Franzen

et al . Mortality and cardiovascular disease in type 1 and type 2 diabetes. New Engl J Med 2017; 376: 1407–1418.

Gerstein

Miller

Byington

et al . Effects of intensive glucose lowering in type 2 diabetes. New Engl J Med 2008; 358: 2545–2559.

Patel

MacMahon

Chalmers

et al . Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med 2008; 358: 2560–2572.

10.

Duckworth

Abraira

Moritz

et al . Glucose control and vascular complications in veterans with type 2 diabetes. New Engl J Med 2009; 360: 129–139.

11.

Zinman

Wanner

Lachin

et al . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl J Med 2015; 373: 2117–2128.

12.

Neal

Perkovic

Mahaffey

et al . Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Engl J Med 2017; 377: 644–657.

13.

Marso

Daniels

Brown-Frandsen

et al . Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl J Med 2016; 375: 311–322.

14.

Marso

Bain

Consoli

et al . Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New Engl J Med 2016; 375: 1834–1844.

15.

Abdul-Ghani

DeFronzo

Del Prato

et al . Cardiovascular disease and type 2 diabetes: has the dawn of a new era arrived? Diabetes Care 2017; 40: 813–820.

16.

Dormandy

Charbonnel

Eckland

et al . Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitazone clinical trial in macrovascular events): a randomized controlled trial. Lancet 2005; 366: 1279–1289.

17.

Kernan

Viscoli

Furie

et al . Pioglitazone after ischemic stroke or transient ischemic attack. New Engl Med 2016; 374: 1321–1331.

18.

DeFronzo

Chilton

Norton

et al . Revitalization of pioglitazone: the optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor. Diabetes Obes Metab 2016; 18: 454–462.

19.

DeFronzo

RA.

Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab 2017; 19: 1353–1362.

20.

Rosenstock

Vico

Wei

et al . Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012; 35: 1473–1478.

21.

Lincoff

Wolski

Nicholls

et al . Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298: 1180–1188.

22.

De Jong

Vander Worp

Vander Graaf

et al . Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovascular Diabetology 2017; 16: 134.

23.

Erdmann

Harding

Lam

et al . Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab 2016; 18: 266–273.

24.

Morgan

Poole

Evans

et al . What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes. J Clin Endocr Metab 2012; 97: 4605–4612.

25.

Strongman

Christopher

Majak

et al . Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study. BMJ Open Diabetes Res Care 2018; 6: e000481.

26.

Yang

Vallarino

Bron

et al . A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study. Curr Med Res Opin 2014; 30: 2223–2231.

27.

Nissen

Nicholls

Wolski

et al . Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299: 1561–1573.

28.

Mazzone

Meyer

Feinstein

et al . Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006; 296: 2572–2581.

29.

Gast

Tjeerdema

Stijnen

et al . Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS ONE 2012; 7: e52036.

30.

Erdmann

Dormandy

Charbonnel

et al . The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) study. J Am Coll Cardiol 2007; 49: 1772–1780.

31.

Wilcox

Bousser

Betteridge

et al . Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitazone clinical trial in macrovascular events 04). Stroke 2007; 38: 865–873.

32.

American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003; 26: 3333–3341.

33.

Dormandy

Betteridge

Schernthaner

et al . Impact of peripheral arterial disease in patients with diabetes–results from PROactive (PROactive 11). Atherosclerosis 2009; 202: 272–281.

34.

Yaghi

Furie

Viscoli

et al . Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS trial (insulin resistance intervention after stroke). Circulation 2018; 137: 455–463.

35.

Young

Viscoli

Inzucchi

et al . Cardiac outcomes after ischemic stroke or transient ischemic attack: effects of pioglitazone in patients with insulin resistance without diabetes mellitus. Circulation 2017; 135: 1882–1893.

36.

CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–1339.

37.

Benavente

Hart

McClure

et al . Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. New Engl J Med 2012; 367: 817–825.

38.

Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. Erratum in BMJ 2002; 324: 141.

39.

Amarenco

Bogousslavsky

Callahan

III et al . High-dose atorvastatin after stroke or transient ischemic attack. New Engl J Med 2006; 355: 549–559.

40.

Tzoulaki

Molokhia

Curcin

et al . Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 2009; 339: b4731.

41.

Liao

Saver

et al . Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2017; 7: e013927.

42.

Morgan

Inzucchi

Pulles

et al . Impact of treatment with pioglitazone on stroke outcomes: a real world database analysis. Diabetes Obes Metab 2018; 20: 2140–2147.

43.

Marx

Wohrle

Nusser

et al . Pioglitazone reduces neointima volume after coronary stent implantation: a randomized, placebo-controlled, double-blind trial in nondiabetic patients. Circulation 2005; 112: 2792–2798.

44.

Nishio

Sakurai

Kusuyama

et al . A randomized comparison of pioglitazone to inhibit restenosis after coronary stenting in patients with type 2 diabetes. Diabetes Care 2006; 29: 101–106.

45.

Riche

Valderrama

Henyan

NN.

Thiazolidinediones and risk of repeat target vessel revascularization following percutaneous coronary intervention: a meta-analysis. Diabetes Care 2007; 30: 384–388.

46.

Vaccaro

Masulli

Nicolucci

et al . Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endo 2017; 5: 887–897.

47.

Basu

Jensen

McCann

et al . Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetes. Diabetes Care 2006; 29: 510–514.

48.

Clarke

Solis-Herrera

Molina-Wilkins

et al . Pioglitazone improves left ventricular diastolic function in subjects with diabetes. Diabetes Care 2017; 40: 1530–1536.

49.

van der Meer

Rijzewijk

de Jong

et al . Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 2009; 119: 2069–2077.

50.

Horio

Suzuki

et al . Pioglitazone improves left ventricular diastolic function in patients with essential hypertension. Am J Hypertens 2005; 18: 949–957.

51.

Young

Viscoli

Schwartz

et al . Heart failure after ischemic stroke or transient ischemic attack in insulin-resistant patients without diabetes mellitus treated with pioglitazone. Circulation 2018; 138: 1210–1220.

52.

Shiomi

Tsutsui

Hayashidani

et al . Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002; 106: 3126–3132.

53.

Terui

Goto

Katsuta

et al . Effect of pioglitazone on left ventricular diastolic function and fibrosis of type III collagen in type 2 diabetic patients. J Cardiol 2009; 54: 52–58.

54.

Zhang

Korantzopoulos

et al . Thiazolidinedione use and atrial fibrillation in diabetic patients: a meta-analysis. BMC Cardiovasc Disor 2017; 17: 96.

55.

DeFronzo

RA.

Banting Lecture: from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58: 773–795.

56.

Schernthaner

Currie

Schernthaner

GH.

Do we still need pioglitazone for the treatment of type 2 diabetes? A risk-benefit critique in 2013. Diabetes Care 2013; 36: S155–S161.

57.

DeFronzo

Mehta

Schnure

JJ.

Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus. Hosp Pract 2013; 41: 132–147.

58.

Eldor

DeFronzo

Abdul-Ghani

In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care 2013; 36: S162–S174.

59.

Promrat

Lutchman

Uwaifo

et al . A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004; 39: 188–196.

60.

Belfort

Harrison

Brown

et al . A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. New Engl J Med 2006; 355: 2297–2307.

61.

Sanyal

Chalasani

Kowdley

et al . Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New Engl J Med 2010; 362: 1675–1685.

62.

Cusi

Orsak

Bril

et al . Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016; 165: 305–315.

63.

Bays

Mandarino

DeFronzo

RA.

Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocr Metab 2004; 89: 463–478.

64.

Bays

Gonzalez-Campoy

Bray

et al . Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther 2008; 6: 343–368.

65.

Miyazaki

Mandarino

et al . Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 2003; 52: 1943–1950.

66.

Coletta

Sriwijitkamol

Wajcberg

et al . Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia 2009; 52: 723–732.

67.

Bajaj

Suraamornkul

Piper

et al . Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocr Metab 2004; 89: 200–206.

68.

Brown

Silvestre

et al . Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106: 523–531.

69.

Collins

Meehan

Kintscher

et al . Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscl Throm Vas 2001; 21: 365–371.

70.

Calkin

Forbes

Smith

et al . Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscl Throm Vas 2005; 25: 1903–1909.

71.

Saremi

Schwenke

Buchanan

et al . Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscl Throm Vas 2013; 33: 393–399.

72.

Yki-Jarvinen

Thiazolidinediones. New Engl J Med 2004; 351: 1106–1118.

73.

Law

Goetze

et al . Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation 2000; 101: 1311–1318.

74.

Orasanu

Ziouzenkova

Devchand

et al . The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 2008; 52: 869–881.

75.

Tontonoz

Nagy

Alvarez

et al . PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998; 93: 241–252.

76.

Jiang

Ting

Seed

. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–86.

77.

Marx

Schonbeck

Lazar

et al . Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998; 83: 1097–1103.

78.

Abdul-Ghani

DeFronzo

RA.

Is it time to change the type 2 diabetes treatment paradigm? Yes! GLP-1 RAs should replace metformin in the type 2 diabetes algorithm. Diabetes Care 2017; 40: 1121–1127.

79.

Hanley

Williams

Stern

et al . Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002; 25: 1177–1184.

80.

Isomaa

Almgren

Tuomi

et al . Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683–689.

81.

Bonora

Kiechl

Willeit

et al . Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck Study. Diabetes Care 2007; 30: 318–324.

82.

Howard

O’Leary

Zaccaro

et al . Insulin sensitivity and atherosclerosis: the Insulin Resistance Atherosclerosis Study (IRAS) investigators. Circulation 1996; 93: 1809–1817.

83.

Bonora

Formentini

Calcaterra

et al . HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002; 25: 1135–1141.

84.

Hedblad

Nilsson

Janzon

et al . Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects: results from a cross-sectional study in Malmo, Sweden. Diabetic Med 2000; 17: 299–307.

85.

DeFronzo

Ferrannini

Groop

et al . Type 2 diabetes mellitus. Nat Rev Dis Primers 2015; 1: 15019.

86.

DeFronzo

Abdul-Ghani

MA.

Preservation of beta-cell function: the key to diabetes prevention. J Clin Endocr Metab 2011; 96: 2354–2366.

87.

Ferrannini

Gastaldelli

Miyazaki

et al . Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocr Metab 2005; 90: 493–500.

88.

Abdul-Ghani

Jenkinson

Richardson

et al . Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006; 55: 1430–1435.

89.

Gastaldelli

Gaggini

DeFronzo

RA.

Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the San Antonio Metabolism Study. Diabetes 2017; 66: 815–822.

90.

Groop

Bonadonna

DelPrato

et al . Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989; 84: 205–213.

91.

Belfort

Mandarino

Kashyap

et al . Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005; 54: 1640–1648.

92.

Bajaj

Pratipanawatr

Berria

et al . Free fatty acids reduce splanchnic and peripheral glucose uptake in patients with type 2 diabetes. Diabetes 2002; 51: 3043–3048.

93.

Kashyap

Belfort

Gastaldelli

et al . A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003; 52: 2461–2474.

94.

Bajaj

Baig

Suraamornkul

et al . Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocr Metab 2010; 95: 1916–1923.

95.

Miyazaki

Mahankali

Matsuda

et al . Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001; 24: 710–719.

96.

Miyazaki

DeFronzo

RA.

Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab 2008; 10: 1204–1211.

97.

Gastaldelli

Miyazaki

Mahankali

et al . The effect of pioglitazone on the liver: role of adiponectin. Diabetes Care 2006; 29: 2275–2281.

98.

Gastaldelli

Casolaro

Ciociaro

et al . Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients. Am J Physiol: Endoc M 2009; 297: E225–E230.

99.

Gastaldelli

Ferrannini

Miyazaki

et al . Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol: Endoc M 2007; 292: E871–E883.

100.

DeFronzo

Tripathy

Schwenke

et al . Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates. Diabetes 2013; 62: 3920–3926.

101.

Daniele

Abdul-Ghani

DeFronzo

RA.

What are the pharmacotherapy options for treating prediabetes?

Expert Opin Pharmaco 2014; 15: 2003–2018.

102.

DeFronzo

Tripathy

Schwenke

et al . Pioglitazone for diabetes prevention in impaired glucose tolerance. New Engl J Med 2011; 364: 1104–1115.

103.

DeFronzo

Tripathy

Abdul-Ghani

et al . The disposition index does not reflect beta-cell function in IGT subjects treated with pioglitazone. J Clin Endocr Metab 2014; 99: 3774–3781.

104.

Loomba

Sanyal

AJ.

The global NAFLD epidemic. Nat Rev Gastro Hepat 2013; 10: 686–690.

105.

Caldwell

Argo

The natural history of non-alcoholic fatty liver disease. Digest Dis 2010; 28: 162–168.

106.

Bugianesi

Vanni

Marchesini

NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diabetes Rep 2007; 7: 175–180.

107.

Portillo

Yavuz

Bril

et al . Role of insulin resistance and diabetes in the pathogenesis and treatment of nonalcoholic fatty liver disease. Curr Hepatol Rep 2014; 13: 159–170.

108.

Ortiz-Lopez

Lomonaco

Orsak

et al . Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care 2012; 35: 873–878.

109.

Bril

Sninsky

Baca

et al . Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin Endocr Metab 2016; 101: 644–652.

110.

Targher

Bertolini

Padovani

et al . Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30: 1212–1218.

111.

Neuschwander-Tetri

Brunt

Wehmeier

et al . Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38: 1008–1017.

112.

Ratziu

Giral

Jacqueminet

et al . Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology 2008; 135: 100–110.

113.

Aronoff

Rosenblatt

Braithwaite

et al . Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study: the Pioglitazone 001 Study Group. Diabetes Care 2000; 23: 1605–1611.

114.

Pioglitazone (marketed as Actos, Actoplus Met, Duetact, and Oseni) information, www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109136.htm (accessed 17 August 2017).

115.

Nesto

Bell

Bonow

et al . Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108: 2941–2948.

116.

Miyazaki

Mahankali

Matsuda

et al . Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocr Metab 2002; 87: 2784–2791.

117.

Sarruf

Nguyen

et al . Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 2009; 150: 707–712.

118.

Wang

YX.

PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 2010; 20: 124–137.

119.

Patti

Butte

Crunkhorn

et al . Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. P Natl Acad Sci USA 2003; 100: 8466–8471.

120.

Puigserver

Spiegelman

BM.

Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003; 24: 78–90.

121.

Zhou

Grayburn

Karim

et al . Lipotoxic heart disease in obese rats: implications for human obesity. P Natl Acad Sci USA 2000; 97: 1784–1789.

122.

Doehner

Erdmann

Cairns

et al . Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. Int J Cardiol 2012; 162: 20–26.

123.

Erdmann

Song

Spanheimer

et al . Observational follow-up of the PROactive study: a 6-year update. Diabetes Obes Metab 2014; 16: 63–74.

124.

Einhorn

Rendell

Rosenzweig

et al . Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study: the Pioglitazone 027 Study Group. Clin Ther 2000; 22: 1395–1409.

125.

Abdul-Ghani

Puckett

Triplitt

et al . Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes: results from the efficacy and durability of initial combination therapy for type 2 diabetes (EDICT): a randomized trial. Diabetes Obes Metab 2015; 17: 268–275.

126.

Abdul-Ghani

Migahid

Megahed

et al . Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: the Qatar Study. Diabetes Care 2017; 40: 325–331.

127.

Mudaliar

Chang

Henry

RR.

Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications. Endocr Pract 2003; 9: 406–416.

128.

Guan

Hao

Cha

et al . Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat Med 2005; 11: 861–866.

129.

Kahn

Haffner

Heise

et al . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New Engl J Med 2006; 355: 2427–2443.

130.

US Food and Drug Administration Safety Alert Actos (pioglitazone), https://www.fda.gov/drugs/drugsafety/ucm109136.htm (accessed 18 January 2019).

131.

Betteridge

DJ.

Thiazolidinediones and fracture risk in patients with type 2 diabetes. Diabetic Med 2011; 28: 759–771.

132.

Bodmer

Meier

Kraenzlin

et al . Risk of fractures with glitazones: a critical review of the evidence to date. Drug Safety 2009; 32: 539–547.

133.

Lewis

Ferrara

Peng

et al . Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34: 916–922.

134.

Lewis

Habel

Quesenberry

et al . Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015; 314: 265–277.

135.

Levin

Bell

Sund

et al . Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015; 58: 493–504.