Glitazones improve glycaemic control in type 2 diabetes mellitus (T2DM) by increasing whole-body insulin sensitivity. They can cause fluid retention and are, therefore, contraindicated in heart failure. A 2007 meta-analysis linked rosiglitazone with an increased risk of myocardial infarction, leading to its European marketing authorisation being suspended in 2010. Pioglitazone has demonstrated cardiovascular safety for atherosclerotic events in a large, randomised, placebo-controlled trial. A 2016 study in patients with insulin resistance and recent cerebrovascular event showed pioglitazone was associated with reduced risk of further stroke or transient ischaemic attack when compared with placebo, as well as reduced diabetes incidence.
Pharmacology
Thiazolidinediones (glitazones) are agonists of the peroxisome-proliferator-activated receptor γ (PPARγ). PPARγ is expressed in adipose tissue, where it is most abundant, and other sites, including pancreatic beta cells and vascular endothelium.1 Ligand binding at PPARγ regulates transcription of target genes that regulate fatty acid metabolism, glucose uptake, adipocyte differentiation and intravascular lipolysis.1 Glitazones promote lipogenesis in adipose tissue, resulting in reduced serum free fatty acid concentrations, reduced hepatic fat content and increased hepatic and peripheral insulin sensitivity.1 Table 1 describes the glitazone drug class.2
Pioglitazone causes an average fall in glycosylated haemoglobin (HbA1c) of 0.6% to 1.2%, with a low risk of hypoglycaemia. It is recommended by the Scottish Intercollegiate Guidelines Network (SIGN) and the National Institute for Health and Care Excellence (NICE) as a second- or third-line oral treatment for type 2 diabetes mellitus (T2DM) in combination with metformin and/or sulphonylurea.3,4 If metformin is not tolerated, NICE also recommends pioglitazone as monotherapy or dual therapy in combination with a dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitor.4
Glitazones can cause fluid retention via a renal mechanism, and increase plasma volume, which may unmask previously unrecognised heart failure.5 Peripheral oedema develops in 3% to 7% of patients taking glitazones, increasing up to 14% to 15% when administered alongside insulin.6 Pioglitazone is, therefore, contraindicated in all patients with current or previous heart failure, and caution should be exercised in patients with risk factors for this condition, for example advanced age or previous myocardial infarction.
Rosiglitazone and pioglitazone have been shown to have significantly different effects on plasma lipids in patients with T2DM. One randomised trial demonstrated that triglyceride concentrations were significantly reduced with pioglitazone but increased by rosiglitazone.7 Pioglitazone was also associated with a greater increase in high-density lipoprotein (HDL)-cholesterol concentration, a smaller increase in low-density lipoprotein (LDL)-cholesterol concentration and a significant increase in LDL particle size compared with rosiglitazone. Increased LDL particle size is thought to be a more favourable lipid phenotype. These mechanisms may contribute to the more beneficial cardiovascular outcomes observed with pioglitazone treatment (table 2).
History of rosiglitazone
The cardiovascular safety of rosiglitazone was called into question in a meta-analysis published in 2007.8 The article, comprising data from 42 randomised trials comparing rosiglitazone to placebo or an active comparator, demonstrated an association between rosiglitazone and an increased risk of myocardial infarction (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.03 to 1.98; p=0.03). The risk of cardiovascular death was also increased but did not reach statistical significance (OR 1.64; 95% CI 0.98 to 2.74; p=0.06).
The RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial, published in 2009, was a post-marketing cardiovascular outcome trial designed to evaluate the cardiovascular safety of rosiglitazone.9 This open-label, non-inferiority trial randomised 4,447 patients with T2DM on metformin or sulphonylurea to either the addition of rosiglitazone or to a combination of metformin and sulphonylurea. Over a mean five-year follow-up period, there was no difference observed in the risk of myocardial infarction, stroke or cardiovascular death between groups. However, rosiglitazone was associated with an increased risk of heart failure causing admission to hospital or death. The study was powered to exclude a 20% excess risk of cardiovascular events with rosiglitazone, therefore, it is not known if the drug could be associated with an excess risk below this threshold.
The Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial was established in 2007 as a US Food and Drug Administration (FDA) mandated cardiovascular outcomes trial. It aimed to assess the impact of glitazones on cardiovascular outcomes and the effects of vitamin D on cancers and mortality.10 The study planned to randomise 16,000 patients to receive placebo, rosiglitazone or pioglitazone over 5.5 years follow-up. However, due to growing concerns regarding the cardiovascular safety of rosiglitazone, TIDE was suspended after a mean of 162 days follow-up by the FDA and withdrawal of treatment was required on 23 September 2010.10 On the same date, the European Medicines Agency (EMA) suspended the marketing authorisation of rosiglitazone across Europe. After a period of imposed prescribing restrictions, the FDA concluded there is no compelling evidence that rosiglitazone increases risk of myocardial infarction and it remains licensed for use in the USA.
PROactive
PROactive (Efficacy of Pioglitazone on Macrovascular Outcome in Patients With Type 2 Diabetes) was a large investigator-led study that assessed the cardiovascular effects of pioglitazone in patients with T2DM and established cardiovascular disease.11 There were 5,238 patients randomised to treatment with pioglitazone (dose titrated from 15 mg to 45 mg) or placebo for a mean follow-up period of 34.5 months. Cardiovascular disease was defined as one or more of: myocardial infarction, stroke, percutaneous coronary intervention or coronary artery bypass surgery at least six months prior to randomisation, acute coronary syndrome at least three months prior, coronary artery disease or obstructive peripheral arterial disease. Exclusion criteria included New York Heart Association (NYHA) class II heart failure or above.
The primary end point, a composite of major adverse cardiovascular events (MACE), comprised all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention on the coronary or leg arteries, or amputation above the ankle. There was no significant difference in this primary end point between groups (hazard ratio [HR] 0.90; 95% CI 0.80 to 1.02; p=0.095). The main secondary end point comprised all-cause mortality, nonfatal myocardial infarction and stroke. This outcome was reduced significantly in the pioglitazone group with 301 events compared with 358 events in the placebo group (HR 0.84; 95% CI 0.72 to 0.98; p=0.027). There was a significantly increased rate of oedema (22% vs. 13%) and heart failure (11% vs. 8%) in the pioglitazone group, although heart failure mortality did not differ between groups.
IRIS
IRIS (Insulin Resistance Intervention After Stroke Trial) examined the utility of pioglitazone in 3,876 patients with insulin resistance and a recent (within six months) ischaemic stroke or transient ischaemic attack (TIA).12 Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) index – an estimate of beta-cell function and insulin sensitivity calculated using fasting blood glucose and insulin values. A HOMA-IR threshold ≥3.0 was selected to identify patients with the highest quartile of insulin resistance without diabetes. Patients received pioglitazone (dose titrated to 45 mg) or placebo in a 1:1 ratio over a median follow-up period of 4.8 years. Exclusion criteria included diabetes mellitus (fasting glucose ≥7 mmol/L or HbA1c ≥7.0%), history of heart failure, moderate or severe dependent oedema and history of bladder cancer.
There was a significant reduction in the primary composite outcome of fatal or nonfatal stroke or myocardial infarction in the pioglitazone group compared with the placebo group (9% vs. 11.8%; HR 0.76; 95% CI 0.62 to 0.93; p=0.007). The incidence of a new diagnosis of diabetes was also reduced with 73 (3.8%) cases in the pioglitazone group compared with 149 (7.7%) cases in the placebo group (HR 0.48; 95% CI 0.33 to 0.69; p<0.001). Results were similar when ancillary analyses were undertaken using updated diagnostic criteria for stroke, myocardial infarction and diabetes mellitus. There was no significant difference in all-cause mortality between pioglitazone and placebo groups (7.0% vs. 7.5%; HR 0.93; 95% CI 0.73 to 1.17; p=0.52). Similarly, there was no difference observed in the development of heart failure (3.8% vs. 3.7%; p=0.80) or hospitalisation for heart failure (2.6% vs. 2.2%; p=0.35). Pioglitazone was associated with an increased risk of bone fractures requiring hospitalisation or surgery compared with placebo (5.1% vs. 3.2%; p=0.003).
Discussion
The glitazones remain a controversial drug class within the T2DM formulary. The National Diabetes Audit 2016 showed the number of prescription items for glitazones in England fell from almost 2,500 items in 2007/8 to just over 1,000 items in 2015/16.13 As the European marketing authorisation of rosiglitazone was suspended in 2010, these data essentially demonstrate the trend in pioglitazone use since then. Despite evidence to support the cardiovascular safety of pioglitazone, its prescribing frequency has been impacted by the association with heart failure and fractures, and the widespread availability of newer diabetes therapies with favourable effects on cardiovascular parameters and weight. Although the IRIS trial highlights a potential role for pioglitazone in reducing cardiovascular risk in patients with pre-diabetes, further evidence of safety and efficacy in this setting is required.
The Thiazolidinediones Or Sulfonylureas and Cardiovascular Accidents Intervention Trial (TOSCA.IT) is an ongoing investigator-led trial evaluating the efficacy of pioglitazone versus sulphonylurea as add-on therapy to metformin in T2DM.14 After PROactive, it is the second trial to evaluate the cardiovascular outcomes of pioglitazone treatment in T2DM. The primary outcome is a MACE composite comprising all-cause mortality, nonfatal myocardial infarction, nonfatal stroke and unplanned coronary revascularisation. Heart failure will be examined as a secondary outcome. The study aims to recruit over 3,000 patients with follow-up for 48 months. Presentation of the initial results is anticipated at the European Association for the Study of Diabetes (EASD) meeting in September 2017.
Key messages
- Glitazones improve whole-body insulin sensitivity in type 2 diabetes mellitus (T2DM); they can cause fluid retention and are contraindicated in heart failure
- The European licensing authorisation for rosiglitazone was suspended in 2010 after an association with myocardial infarction was observed in a meta-analysis
- Pioglitazone reduced major cardiovascular events compared with placebo in patients with T2DM and established cardiovascular disease in a large randomised-controlled trial
- A placebo-controlled study in non-diabetic patients with insulin resistance and a recent stroke or transient ischaemic attack (TIA) showed pioglitazone was associated with a reduced risk of further cerebrovascular event and reduced incidence of diabetes
Conflict of interest
EJ: none declared. GMcK: none declared. MF has received payment for lectures and advisory boards from GSK and Takeda.
Editors note
This article is the third in the series ‘drugs for diabetes’. The first article on dipeptidyl peptidase-4 (DPP-4) inhibitors was published in the first issue of 2017 (doi:10.5837/bjc.2017.001). The second article on SGLT2 inhibitors was published in the last issue (doi:10.5837/bjc.2017.010). Subsequent articles in this series will cover Glucagon-like peptide-1 (GLP-1) receptor agonists (doi:10.5837/bjc.2017.030) Older antidiabetic drugs (doi: 10.5837/bjc.2018.007) and glucose-lowering drugs for patients with cardiac disease (doi:10.5837/bjc.2018.016).
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