Thiazolidinediones

Introduction

The thiazolidinediones (TZDs) work mainly to reduce insulin resistance in skeletal muscle, adipose tissue and liver. At least some of their action involves stimulation of nuclear receptors called peroxisome proliferator-activated receptors (PPARs) that regulate gene transcription of a number of proteins involved in glucose and lipid metabolism. There are three types of PPAR receptors: PPARα, PPARβ/α and PPARγ. The TZDs are synthetic activators of PPARγ; this activation is associated with a reduction in insulin resistance. The exact mechanism by which activation of PPARγ improves insulin action is unknown but involves modifications in the expression of specific gene products and activity of pivotal enzymes of insulin signaling. PPARγ is highly expressed in adipose tissue but is also found in other tissues including skeletal muscle, liver, pancreas, macrophages, monocytes and other cells of the vasculature.

Since cardiovascular (CV) disease is the major cause of morbidity and mortality in type 2 diabetes (T2D), one intriguing observation was the ability of the TZDs to reduce CV risk factors, including markers of vascular inflammation. Although they have a positive effect on a broad range of CV risk factors, a correlation with a beneficial effect on CV events has not been consistently demonstrated . Currently, the two marketed TZDs are rosiglitazone and pioglitazone.

Rosiglitazone (Avandia)

Rosiglitazone (Avandia) is currently indicated for use as monotherapy and in combination with SFUs, MET and insulin. Rosiglitazone is also available in fixed-dose single-tablet formulations with either MET (Avandamet) or a glimepiride (Avandaryl).

Although rosiglitazone and its combination formulations are still available in the United States, they currently are used rarely because of extensive restrictions (that have been since removed by the FDA), safety concerns specified in the Black Box Warnings and Cautions and the availability of an alternative drug in this class. The package insert should be consulted before prescribing. Dosage recommendations for Avandia, Avandamet and Avandaryl are included in Table 8-1.

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Pioglitazone (Actos)

Pioglitazone (Actos) is indicated for use as monotherapy or in combination with metformin (MET), sulfonylurea (SFUs), or insulin. Six registration studies (three monotherapy, three combination therapy) formed the basis of the Food and Drug Administration (FDA) approval.

Monotherapy

The monotherapy studies included 865 patients with T2D. In general, there was a -1.4% to -1.6% reduction in glycosylated hemoglobin (A1C) observed with the highest dose of pioglitazone (45 mg/day) over a treatment period of 16 to 26 weeks. Greater reductions of A1C and fasting plasma glucose (FPG) were observed in treatment-naïve patients with a short duration of diabetes. In another study, pioglitazone was compared head-to-head with MET in 206 drug-naïve type 2 diabetic patients (titrated to achieve FPG <126 mg/dL). Pioglitazone was equally as effective as MET in this double-blind 32-week trial (Figure 12-1).

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Combination Therapy

In the combination-therapy studies, pioglitazone or placebo was added to the regimen of patients in whom SFUs, MET, or insulin failed. In these studies, there was a significant 0.8% to 1.3% reduction in the A1C when pioglitazone 30 mg/day was used. Figure 12-2 illustrates the lack of secondary failure with pioglitazone when used as monotherapy and combination therapy. When pioglitazone is added to MET, durable glycemic control is also seen. The combination of pioglitazone and MET is not only effective in reducing the A1C and preventing secondary failure over time, but also positively affects CV risk factors with minimal or no risk for hypoglycemia.

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Pioglitazone Fixed-Dose Combinations (Actoplus Met, Actoplus Met XR, Duetact)

Pioglitazone is currently available in two different fixed-dose, single-tablet formulations containing pioglitazone and MET (Actoplus Met, Actoplus Met XR) or pioglitazone and glimepiride (Duetact).

Actoplus Met

This combination formulation is indicated to improve glycemic control in patients with T2D who are already treated with a combination of pioglitazone and MET or whose diabetes is not adequately controlled with MET alone, and in those patients who have initially responded to pioglitazone alone and require additional glycemic control.

There have been no clinical efficacy studies conducted with Actoplus Met. However, the efficacy and safety of the separate components have been previously established and the coadministration of the separate components has been evaluated for efficacy and safety in two clinical studies that included patients receiving MET, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. As shown in Table 12-1, the combination of pioglitazone 30 mg and MET significantly reduced the mean A1C and mean FPG at week 16 compared with placebo and MET alone. In a 24-week study, both dosage regimens of pioglitazone produced significant reductions from baseline in A1C and FPG at week 24. The reduction in FPG with pioglitazone 45 mg was significantly greater than with pioglitazone 30 mg.

Duetact

This combination formulation is indicated to improve glycemic control as an adjunct to diet and exercise in patients with T2D who are already being treated with a combination of pioglitazone and an SFU or whose diabetes is not adequately controlled with an SFU alone and in those patients who have initially responded to pioglitazone alone and require additional glycemic control.

There have been no clinical efficacy studies conducted with Duetact. However, coadministration of pioglitazone and an SFU, including glimepiride, has been evaluated in two clinical studies in patients with T2D receiving an SFU, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. In a 16-week study, the addition of pioglitazone 15 mg or 30 mg once daily to treatment with an SFU significantly reduced the mean A1C and the mean FPG compared with placebo and an SFU. In a 24-week study, both dosage regimens of pioglitazone plus an SFU significantly reduced mean A1C and FPG from baseline levels.

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Effect on Lipid Levels

Pioglitazone used as monotherapy and in combination resulted in a significant mean percent decrease in triglycerides (up to 15%) and significant mean percent increases in high-density lipoprotein (HDL) (up to 19%) with no change in the low-density lipoprotein (LDL) and total cholesterol levels; however, many of the studies demonstrated a reduction in LDL as well. The difference in effects on the lipoprotein profile depends on the patient population studied and the effect of mechanisms of each drug on the peroxisome proliferator-activated receptor (PPAR) system.

A randomized, 24-week, double-blind trial compared the differential effects of pioglitazone and rosiglitazone on serum lipoprotein particle concentrations in 735 diabetes patients with dyslipidemia. While both treatments increased LDL particle size, pioglitazone had a greater effect. Both treatments increased HDL cholesterol levels. However, pioglitazone increased both total HDL particle concentration and size but rosiglitazone decreased both.

Effect on Cardiovascular Risk Factors

Pioglitazone has also been shown to reduce traditional and nontraditional CV risk factors. Pioglitazone has also been shown to reduce PAI-1 levels and improve the pro­coagulant state. Consistent and sustained reductions in intimal medial thickness have been clearly demonstrated with pioglitazone.

T2D and coronary artery disease have both been identified as conditions associated with inflammation. In addition, pioglitazone, as well as rosiglitazone, has been shown to reduce CRP in patients with T2D (Figure 12-3). Furthermore, A1C there were equivalent reductions in CRP value both in the patients who had a >1% decrease in the A1C value (responders) and those who did not have a large reduction in A1C value (nonresponders).

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The PROactive Study

The Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) was designed to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with T2D. In this prospective, placebo-controlled trial, 5,238 patients with T2D who had evidence of macrovascular disease were randomized to receive pioglitazone (N = 2,605) titrated from 15 mg to 45 mg or placebo (N = 2,633). The primary end point was the composite of all-cause mortality, nonfatal myocardial infarction (MI) (including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. The main secondary end point was the composite of all-cause mortality, nonfatal MI (excluding silent MI) and stroke. The average time of observation was 34.5 months.

Fewer patients in the pioglitazone group had at least one event more in the primary composite end point than did those in the placebo group (19.7% vs 21.7%, respectively; P = 0.095). In their discussion of the results, the investigators opined that the lack of a significant difference in the primary end point was likely related to the fact that when the protocol was designed, it was believed that the need for amputation or coronary or leg revascularization would respond to therapy in a similar way to stroke and MI. This hypothesis, however, did not prove correct in the case of cardiac and leg revascularization, perhaps because these end points are in part determined by the decision to intervene being based on local surgical or medical practice. Therefore, the study may have been underpowered to detect a significant difference in the primary composite end point.

Regarding the main secondary composite end point (the composite of all-cause mortality, nonfatal MI and stroke), significantly fewer patients in the pioglitazone group (11.6%) than in the placebo group (13.3%) experienced at least one of these events (Figure 12-4).

Compared with patients in the placebo group, there was a rapid and sustained decrease in insulin doses in patients in the pioglitazone group who were receiving insulin at study entry (Figure 12-5). By study end, the mean insulin dose was significantly lower with pioglitazone (42 U/d) than with placebo (55 U/d); nevertheless, there was a greater decrease in A1C compared with placebo (−0.93% vs −0.45%). At final visit, insulin had been discontinued in 9% of patients in the pioglitazone group vs 2% in the placebo group. Conversely, of the 3,478 patients who were not receiving insulin at study entry, significantly fewer pioglitazone-treated patients than placebo-treated patients (11% vs 21%, respectively) began to use insulin permanently during the course of the study.

Overall safety and tolerability of pioglitazone were good and no changes in the safety profile of pioglitazone were observed, although edema and weight gain were more frequent compared with placebo. There were significantly more reports of heart failure in the pioglitazone group compared with the placebo group (417 vs 302, respectively); however, these reported events were not adjudicated and therefore possibly overreported. Despite the increase in reported heart failure among pioglitazone-treated patients, the number of deaths from heart failure was similar in both groups (25 and 22, respectively).

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Prescribing Pioglitazone

Dosing of pioglitazone should be titrated up to a maximum effective daily dose of 45 mg as monotherapy and in combination therapy. Pioglitazone is always administered once daily and can be taken without regard to the time of food ingestion. Onset of activity has been observed as early as 2 weeks, with maximum effects seen in 8 to 12 weeks. The FDA has eliminated the need for monitoring liver function every 2 months for the first year after initiating TZD therapy. The current recommendation for liver enzyme monitoring is prior to initiation of therapy and periodically thereafter.

Prescribing Actoplus Met

Actoplus Met is available in two tablet strengths: 15 mg pioglitazone/500 mg MET and 15 mg pioglitazone/850 mg MET.

In patients inadequately controlled on MET monotherapy, Actoplus Met may be initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength qd or bid and gradually titrated after assessing adequacy of therapeutic response. In patients who initially responded to pioglitazone monotherapy but require additional glycemic control, Actoplus Met may be started at either the 15 mg/500 mg or 15 mg/850 mg tablet strength every day (qd), and gradually titrated after assessing adequacy of therapeutic response.

Prescribing Duetact

Duetact is available in two tablet strengths: 30 mg pioglitazone/2 mg glimepiride or 30 mg pioglitazone/4 mg glimepiride.

In patients currently on glimepiride monotherapy, Duetact may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths qd, and adjusted after assessing therapeutic response. The usual starting dose of Duetact in patients currently on pioglitazone monotherapy is 30 mg/2 mg qd. When switching patients from combination therapy of pioglitazone plus glimepiride as separate tablets, Duetact may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of pioglitazone and glimepiride already being taken. Patients who are not controlled with pioglitazone 15 mg in combination with glimepiride should be carefully monitored when switched to Duetact. Since no exact dosage relationship exists between glimepiride and the other SFUs, the starting dose of Duetact should be limited to 30 mg/2 mg qd in patients currently receiving monotherapy with an SFU other than glimepiride.

Side Effects With TZDs

Liver Toxicity

After extensive use of rosiglitazone and pioglitazone in patients worldwide, liver toxicity does not appear to be an important clinical problem. Baseline liver function tests (LFTs) should be done and if abnormal, an investigation should be initiated to determine the primary cause. Often steatohepatitis, or a fatty liver, may be the culprit.

Therapy with TZDs should not be initiated in patients with increased baseline liver enzyme levels (alanine aminotransferase [ALT] >2.5 times the upper limit of normal). In all patients, it is recommended that liver enzymes be monitored prior to initiation of TZD therapy and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels 1 to 2.5 times the upper limit of normal) at baseline or during therapy with TZDs should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with a TZD in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3 times the upper limit of normal in patients taking TZDs, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3 times the upper limit of normal, TZD therapy should be discontinued.

Congestive Heart Failure (CHF) and Edema

The FDA has issued a boxed warning stating that, since TZDs can cause or exacerbate CHF, their use in patients with established NYHA Class III or IV heart failure is contraindicated. Furthermore, their use is not recommended in patients with symptomatic heart failure. Patients already receiving a TZD should be observed carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of the TZD must be considered.

In 2003, an American Diabetes Association (ADA)/American Heart Association (AHA) consensus conference was convened to discuss the issues of fluid retention and CHF as they relate to the use of TZDs. One of the most important statements from the conference was that the presence of edema does not always indicate the presence of CHF. When considering the use of TZDs in diabetic patients, it is always important to ascertain the potential presence of underlying cardiac disease by obtaining a good history of any past medical events (e.g., MI) and use of medications associated with fluid retention (eg, vasodilators, nonsteroidal anti-inflammatory agents, or calcium channel blocker (CCBs)). Risk factors for heart failure in patients treated with TZDs are listed in Table 12-2.

A thorough physical examination is important to look for signs of CHF; documentation of the presence or absence of ankle edema is crucial for comparison after TZD therapy is initiated. Edema is not an absolute contraindication of TZDs and can be treated with a low-dose thiazide diuretic, especially if the blood pressure is not at goal levels.

The use of B-type natriuretic peptide (BNP), which is a marker of ventricular dysfunction, may prove to be valuable when initiating TZDs and in determining whether a patient is at risk for CHF and thus in need of long-term monitoring while taking a TZD.

TZDs have caused preload-induced cardiac hypertrophy in preclinical studies. However, in three FDA-required echocardiographic clinical studies in patients with type 2 no deleterious alterations in cardiac structure or function were observed. These studies were designed to detect a change in left ventricular mass ≥10%.

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CVD and Mortality Risk

A meta-analysis of data from 42 trials that included nearly 28,000 patients indicated that the use of rosiglitazone produced a small but significant increased risk of MI and a small but not statistically significant increased risk of CV death. In November 2007, the FDA updated the Black Box warning in the label for rosiglitazone noting the increased risk of MI seen in that meta-analysis, while also stating that the research on the increased MI risk from rosiglitazone use is inconclusive. Subsequently, numerous other studies, meta-analyses, as well as retrospective “data-mining” studies, reported often-conflicting findings, which resulted in an ongoing controversy whether rosiglitazone is associated with an increased risk of cardiovascular disease (CVD) and mortality. In 2010, the FDA convened an advisory board that concluded that rosiglitazone may remain on the market with more supervision and stronger warnings in response to these data, thus imposing extensive restrictions on the prescription of rosiglitazone.

In contrast, the placebo-controlled, randomized, prospective PROactive trial (discussed above) reported a 10% trend in reduction in total CVD events with pioglitazone compared with placebo. The beneficial trends in events were not present until after 1 year of follow-up, pointing out one of the major limitations in some of the smaller trials with rosiglitazone. Additional data on the CV safety of pioglitazone comes from an independent analysis of the results from a total of 19 trials that enrolled 16,390 patients who were treated from 4 months to 3.5 years. The primary outcome, a composite of death, MI, or stroke, occurred in 375 of 8,554 patients (4.4%) receiving pioglitazone and 450 of 7,836 patients (5.7%) receiving control therapy (HR 0.82). Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR 1.41).

RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) was an open-label trial comparing the addition of rosiglitazone to metformin when either one was added on to a background SFU and the addition of rosiglitazone to SFU when either one was added on to background metformin. The primary objective of the trial was to show noninferiority of rosiglitazone combined with either metformin or SFU to the combination of metformin and SFU on the primary composite endpoint of CV death and CV hospitalizations. The trial met its primary objective with an estimated HR of 0.99 and corresponding 95% CI of (0.85, 1.16), excluding an upper margin of 1.2. A nonsignificant increase in risk of MI was observed in the rosiglitazone arm; but, there was also a nonsignificant reduction in risk of stroke and all-cause mortality in rosiglitazone users.

Results from the RECORD clinical trial showed no elevated risk of heart attack or death in patients being treated with rosiglitazone when compared with standard-of-care diabetes drugs, These data do not confirm the signal of increased risk of heart attacks that was found in the previous meta-analysis, and the formerly imposed restrictions on rosiglitazone use were lifted by the FDA in 2013.

Summary

When used in the appropriate clinical situation, the TZD class of oral agents can have a significant impact on the metabolic management of T2D. The novel mechanism of action of TZDs to improve insulin resistance has unique potential in new-onset T2D. Many of the greatest benefits of these agents may occur in patients who are in the early stages of developing diabetes and premature CV disease. The expanded availability of fixed-dose, single-tablet formulations of combinations of a TZD and MET or an SFU (i.e., glimepiride), provide more convenient administration and potential enhancement of therapy adherence.