Mayday for Dual PPAR Agonists

Once-Hyped Diabetes Therapies in Their Death Throes?
Emerging Technology


Metabolic Syndrome Pioglitazone Bezafibrate PPAR Agonist Avandia 
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Executive summary

The month of May saw the demise of Pargluva™ (muraglitazar; Bristol-Myers Squibb) and Galida™ (tesiglitazar; AstraZeneca), two members of an experimental drug class for type 2 diabetes and metabolic syndrome — the dual peroxisome proliferator-activated receptor (PPAR) agonists. Also known as the glitazars, five members of this class have now been discontinued in phase III trials, mainly for safety reasons. PPAR-alpha (α) and -gamma (γ) play vital roles in controlling energy balance within the body and compounds activating both these receptors were once regarded as potential blockbusters for therapy of type 2 diabetes or the metabolic syndrome. However, it now seems that dual α/γ PPAR agonists may be fundamentally unsafe for pharmacological use.

The wider field of PPAR-activating drugs is far from dead, however, with many novel compounds in development targeting PPAR-α or -γ alone. Furthermore, a recently discovered third type of PPAR, delta (PPAR-δ), appears to play a central role in energy metabolism and may be a better target for treatment of metabolic diseases. Stimulation of PPAR-δ may also counterbalance the adverse effects associated with dual activation of PPAR-α and -γ. Consequently, compounds targeting PPAR-δ alone or all three PPARs (‘pan’ PPAR agonists) are undergoing early stages of development for obesity, type 2 diabetes, metabolic syndrome and dyslipidemia.

The high-risk nature of drug development is exemplified by the recent misfortunes of the dual peroxisome proliferator-activated receptor (PPAR) agonists, experimental compounds that stimulate both the alpha (α) and gamma (γ) PPARs. Once regarded as potential blockbusters for treatment of type 2 diabetes or metabolic syndrome, the May 2006 decisions by AstraZeneca and Bristol-Myers Squibb to drop Galida™ (tesiglitazar) and Pargluva™ (muraglitazar), respectively, mean that five dual PPAR agonists have now failed in late clinical development. With several different types of toxicity emerging in clinical trials, the main issue with this novel drug class seems to be safety. However, despite these recent disappointments, the door is not yet closed on dual PPAR agonists, with several more drug candidates in clinical development.

PPARs — validated drug targets

PPARs are a class of fatty acid-activated transcription factors that play fundamental roles in controlling energy balance in the body, through regulating the expression of proteins involved in metabolism of fats and sugars (see text box). PPAR-α stimulates the expression of several proteins that control the breakdown of fats. Fibrate compounds such as gemfibrozil and bezafibrate — prescribed to treat abnormalities in serum lipids (dyslipidemia) — exert much of their therapeutic effect through binding and stimulation of PPAR-α. A second type, PPAR-γ, triggers the expression of proteins critically involved in control of blood glucose levels and lipid metabolism. Thiazolidinedione drugs such as Actos® (pioglitazone; Eli Lilly) and Avandia® (rosiglitazone; GlaxoSmithKline), whose insulin-sensitizing effects see them widely prescribed to patients with type 2 diabetes, are PPAR-γ agonists. The fact that the clinically established thiazolidinediones and fibrates exert their therapeutic effects through stimulation of PPAR-γ and PPAR-α, respectively, led to interest in developing compounds that can stimulate both types of receptor — the dual α/γ PPAR agonists.

Dual PPAR agonists: more than just glorified combination pills?

Patients with type 2 diabetes commonly have both high blood sugar (hyperglycemia) and a characteristic pattern of dyslipidemia consisting of elevated levels of triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and an excess of small dense low-density lipoprotein cholesterol (sdLDL-C) particles (although overall levels of LDL-C are often normal). Hyperglycemia can result in damage to the kidneys, nerves and eyes, whereas diabetic dyslipidemia greatly increases the risk for cardiovascular disease (CVD). Patients with type 2 diabetes are commonly prescribed fibrates (PPAR-α agonists) to reduce triglycerides and increase HDL-C, and thiazolidinediones (PPAR-γ agonists) to control hyperglycemia. Consequently, a logical next step would be to combine these two therapies into one medication — i.e. dual α/γ PPAR agonists that have both fibrate- and thiazolidinedione-like effects.

An advantage of this approach would be to reduce the number of pills patients need to take. Although this may appear somewhat trivial, patients prescribed multiple medications — such as those with diabetes — often do not consistently take all doses. This lack of compliance can have important consequences for therapeutic efficacy in a real-world setting. Another driver for development of dual PPAR agonists is the desire to develop more potent drugs, particularly for stimulation of PPAR-α (as fibrates have relatively weak effects on that receptor). It has also been suggested that dual PPAR agonists would be useful for treating the metabolic syndrome, a clustering of metabolic abnormalities that individually and collectively increase the risk of type 2 diabetes and CVD. Core features of the metabolic syndrome include glucose intolerance/insulin resistance (‘pre-diabetes’) and a pattern of dyslipidemia very similar to that of patients with type 2 diabetes. Thus, dual PPAR agonists would target two of the major risk factors in patients with metabolic syndrome.

Safety concerns sink first five

On 4 May, AstraZeneca announced that it had discontinued development of its dual PPAR agonist Galida because of indications the drug could cause kidney damage. On 18 May, Bristol-Myers Squibb dropped its own dual PPAR agonist Pargluva after it became apparent that additional long-term studies would be required to establish the safety of the drug. Previously, in October 2005, the US FDA had issued an approvable letter for Pargluva as a monotherapy and in combination with metformin for treatment of type 2 diabetes. However, the agency also requested additional studies to clarify the cardiovascular safety profile of the compound because of data suggesting that Pargluva increased the risk of CVD and associated deaths in patients with type 2 diabetes.[1] Bristol-Myers Squibb decided not to conduct such studies, apparently for commercial and strategic reasons.

The discontinuation of Galida and Pargluva means five dual PPAR agonists have now failed clinical development since 2003, all essentially for safety reasons (see table I). Previously, Takeda had dropped imiglitazar in phase III development, after clinically significant elevations in liver enzymes were observed in some treated patients. Earlier, Novo Nordisk and Merck & Co. discontinued phase III trials of ragaglitazar and MK-767, respectively, after animal data showing long-term treatment with these compounds might cause tumors. This suggestion of carcinogenicity prompted the FDA to announce in July 2004 that it would not allow any clinical trials of dual PPAR agonists lasting more than 6 months, i.e. phase III trials, unless 2-year rodent toxicity data was available.
Table I

Dual PPAR agonists discontinued in advanced clinical developmenta

With the benefit of hindsight, some of these adverse effects were not entirely surprising. PPAR-γ agonists currently prescribed for diabetes, such as Avandia and Actos, are known to be associated with weight gain, fluid retention and swelling in peripheral tissues, as well as a small increase in the risk of heart failure. Furthermore, an earlier PPAR-γ agonist for type 2 diabetes, Rezulin® (troglitazone; Pfizer), was withdrawn from the market due to rare cases of serious liver toxicity. It had been hoped that simultaneous stimulation of PPAR-α by dual PPAR agonists might offset the weight gain and other adverse effects associated with stimulation of PPAR-γ alone. However, in a phase II trial of the ill-fated Pargluva, weight gain and swelling were actually more common in patients treated with the drug than in those treated with Actos.[2]

Uncertain future for dual PPAR agonists

The safety issues raised by the failure of the first five dual PPAR agonists to reach advanced clinical development have called into question the viability of the drug class as a pharmaceutical technology. The major challenge appears to be that PPAR-α and -γ each control the expression of a large number of proteins involved in a variety of biological processes, not just in control of glucose and lipid metabolism. The function of many of these proteins has yet to be determined. Thus, simultaneous pharmacological stimulation of both PPAR-α and -γ may have unavoidable toxicities as well as desired therapeutic effects.

Renowned cardiologist and cardiovascular drug researcher Dr Steven Nissen from the Cleveland Clinic Foundation recently commented that “the toxicity from these dual PPAR agents may reflect that they are relatively blunt treatments, activating or suppressing dozens of genes. The functional effects of most of these gene products remain unknown. It may turn out that the very broad actions of dual PPARs do not permit separation of clinical efficacy from serious toxicity.”[3]

Furthermore, some diabetes researchers have suggested that dual PPAR agonists are just ‘me too’ drugs that offer few advantages over fibrates and thiazolidinediones. Despite these issues, the drug class has not yet been entirely abandoned by pharmaceutical companies, with several more dual PPAR agonists in earlier stages of clinical development (see table II).
Table II

Dual PPAR agonists in clinical developmenta

Next-generation PPAR drugs — delta and ‘pan’ agonists

Despite the problems with dual PPAR agonists, there is no suggestion of abandoning the wider class of PPAR-activating drugs. PPAR-α and PPAR-γ agonists — fibrates and thiazolidinediones, respectively — will continue to be used clinically, and many novel agents from these classes are in clinical development. Furthermore, a real breakthrough may come with compounds that stimulate a third form of receptor, PPAR-delta (δ). Although the biological function of PPAR-δ was largely unknown until recently, studies have shown that it stimulates breakdown of fats by muscle and adipose tissues and can suppress the liver’s secretion of glucose into the bloodstream. Treatment of obese animals with PPAR-δ agonists reduces fat tissue, improves insulin sensitivity and increases HDL levels. Therefore, PPAR-δ agonists are considered to have potential for treatment of obesity, dyslipidemia, metabolic syndrome and type 2 diabetes.

Furthermore, simultaneous triple activation of PPAR-δ, PPAR-α and PPAR-γ may prevent the weight gain which typically accompanies pure PPAR-γ and dual PPAR-α/γ agonists. Consequently, PPAR-δ agonists and triple (‘pan’) agonists targeting all three forms of PPAR are under investigation, although development is still at early stages (see table III). Supporting the development of pan-PPAR agonists is the fact that bezafibrate, which has been prescribed to patients for around 4 decades, was recently found to activate all three types of PPAR. Bezafibrate has been proven to reduce the number of coronary events such as heart attacks in patients with metabolic syndrome or type 2 diabetes, and to delay the development of type 2 diabetes in patients with metabolic syndrome. However, bezafibrate is a relatively weak pan-PPAR agonist and there is hope that more potent compounds can be developed.
Table III

Next-generation PPAR agonistsa

Looking ahead

The dual PPAR agonist story represents a cautionary tale for drug developers considering targeting transcription factors that control the expression of many genes. Despite the gloom surrounding the drug class, it is possible that a clinically acceptable dual PPAR agonist drug may yet emerge (although pharma companies may not be prepared to take the risk for too much longer). In the longer term, compounds targeting PPAR-δ or pan-agonists targeting all three PPARs may prove to be a safer bet for treatment of type 2 diabetes, metabolic syndrome, obesity and dyslipidemia.

Energy switches — the biology of PPARs

The peroxisome proliferator-activated receptors (PPARs) are three related proteins (α, γ, δ) that function as transcription factors in the nucleus of the cell, binding genomic DNA and altering the expression of target genes. Members of the steroid hormone nuclear receptor family, PPARs are activated by natural fatty acids, as well as synthetic pharmaceutical ligands.

PPARs were discovered in the late 1980s when fibrates, used clinically to treat dyslipidemia, were observed to cause proliferation of peroxisomes within rat liver cells, an effect subsequently shown to be mediated through binding and stimulation of PPAR-α. The PPAR-α isoform is expressed in high levels in the liver and skeletal muscle and controls the expression of many proteins involved in the transport and breakdown of fatty acids, such as acyl CoA oxidase, acyl CoA synthetase, and lipoprotein lipase.

It was subsequently discovered that the insulin-sensitizing effects of the thiazolidinediones prescribed for type 2 diabetes largely result from stimulation of a second PPAR isoform, PPAR-γ. Large amounts of PPAR-γ are produced in fat tissue, where it controls the expression of proteins involved in glucose metabolism— such as the GLUT4 glucose transporter — as well as adipocyte differentiation and maturation.

The third member of the family, PPAR-delta (δ) or PPAR-δ/beta (β), is produced in most cells of the body and also appears to play a fundamental role in energy metabolism.


  1. 1.
    Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005; 294 (20): 2581–6PubMedCrossRefGoogle Scholar
  2. 2.
    Kendall DM, Rubin CJ, Mohideen P, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diabetes Care 2006; 29: 1016–23PubMedCrossRefGoogle Scholar
  3. 3.
    Nissen SE. Adverse events related to muraglitazar use in diabetes: reply. JAMA 2006; 295 (17): 1998CrossRefGoogle Scholar

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© Adis Data Information BV 2006

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