Insulin resistance (IR) is widely recognized as a core physiologic defect contributing to the development of both type 2 diabetes and cardiovascular disease (CVD).[1,2] The majority of individuals with type 2 diabetes are known to be insulin-resistant, and this IR, when coupled with an inadequate pancreatic beta-cell response, results in hyperglycemia.[1] Both clinical and epidemiologic data support the association between IR and an increase in CVD risk.[3-6] IR is associated with the development of a cluster of characteristic CVD risk factors, including hypertension; an atherogenic dyslipidemia (characterized by low high-density lipoprotein cholesterol [HDL-C], increased triglycerides, and an increase in the prevalence of small, dense low-density lipoprotein [LDL] particles); and a proinflammatory, prothrombotic vascular environment,[7-9] all of which likely contribute to the increase in CVD risk observed.

Given the accepted role of IR in the pathogenesis of diabetes and CVD, therapies that improve insulin action are used commonly for the management of hyperglycemia in diabetes. Moreover, there is significant interest in diabetes therapies that may limit CVD risk. Specifically, the impact of peroxisome proliferator activating receptor (PPAR)-gamma agonists, such as the thiazolidinediones (TZDs) on both diabetes control and CVD risk, has been widely discussed. These PPAR activators are well known to improve glucose control -- in great part by improving insulin action in the periphery -- and may improve a number of CVD risk factors, including hypertension, dyslipidemia, and the vascular, hemodynamic, and hemostatic abnormalities that are common in those with diabetes.[9]

PPARs: An Update From the European Association for the Study of Diabetes 2005 Meeting
Although PPAR agonists possess myriad effects on both insulin sensitivity and vascular behavior, it has not been clearly established whether these agents can reduce the risk for CVD events in patients with diabetes. Although improvement in many CVD risk factors has been reported -- and numerous reports in both clinical trials and animal studies suggest a reduction in vascular injury with PPAR-gamma agonist therapy -- there have been no prospective, randomized trials assessing the impact of TZD therapy on CVD risk.
TZDs and PPARs were widely featured in reports at this year's European Association for the Study of Diabetes (EASD) annual meeting. The most anticipated of these was the report of the first prospective outcome trial of PPAR therapy (pioglitazone) in the treatment of patients at high risk for CVD. The results of this large-scale clinical trial -- as well as a summary of other key studies assessing PPARs -- are detailed below. These reports not only include clinical and metabolic data from studies of TZDs; they also include several detailed descriptions of safety and efficacy of the PPARs and a report on the newest class of PPARs -- the so-called dual PPARs or glitazars.

TZDs and CVD Risk: The PROactive Study

The results of the long-anticipated PROactive study (Prospective PioglitAzone Clinical Trial in MacroVascular Events) were presented by Professor John Dormandy, St. George's Hospital, London, United Kingdom, and colleagues on September 12, 2005.[10] This study was a randomized, double-blind, placebo-controlled trial specifically assessing the impact of pioglitazone therapy on CVD risk in patients with type 2 diabetes who are known to be at high risk for cardiovascular events.[11] Over 5200 subjects were enrolled in PROactive. All patients received "optimized treatment" of their diabetes based on International Diabetes Federation guidelines with any other glucose-lowering therapy (including insulin). In addition, half of the subjects were randomized to receive maximal-dose pioglitazone therapy, which was force-titrated to a dose of 45 mg daily in 93% of subjects. In addition to optimizing glycemic control in all subjects, the investigators were encouraged to target current lipid and blood pressure targets. A majority of patients were treated with aspirin (> 70%) and either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (again over 70%). A significant fraction (42%) of subjects received statin therapy, and the use of statin therapy increased during the 3 years of the study (with 55% of patients in both treatment groups receiving statins by study completion).

Subjects were followed over approximately 3 years, and the rates of major CVD events were recorded. The primary end point of PROactive was a composite of death, nonfatal myocardial infarction (MI), acute coronary syndrome, coronary intervention (either coronary artery bypass grafting or percutaneous interventions), stroke, major leg amputation, or leg revascularization. A series of predefined secondary end points were also included, in particular, the so-called principal secondary end point of all-cause mortality, nonfatal MI, and stroke.

PROactive Results.

The mean follow-up for subjects in PROactive was a relatively short 2.8 years. Despite efforts to manage subjects in each group to the same treatment targets, a number of key metabolic variables were significantly improved in subjects randomized to pioglitazone therapy. Glycosylated hemoglobin (A1C) levels were, on average, .5% lower in pioglitazone-treated subjects (6.9% vs 7.5%), and these patients were less likely to require insulin therapy (3% vs 12%). There were also modest but significant differences in both blood pressure and lipid levels (with triglycerides 13% lower and HDL-C 8.9% higher in the pioglitazone subjects).

Major cardiovascular events were reduced in those randomized to pioglitazone treatment. However, this reduction did not achieve statistical significance (P > .09). The rates of the defined composite macrovascular end point were reduced by approximately 10%, from 23.5% (over 3 years) in the placebo group to 21.0% in the active treatment group. The investigators also reported the results from the principal secondary end point of all-cause mortality, nonfatal MI, or stroke. Pioglitazone treatment was associated with a 16% relative risk reduction (3-year event rates of 14.4% with placebo vs 12.3% with pioglitazone) for this critical secondary end point, and this difference was statistically significant (P = .027).
Overall, treatment with pioglitazone was well tolerated -- an important feature in this high-risk group of subjects. A number of safety issues were considered in detail by the investigators. Rates of edema were higher in the pioglitazone group, and hospitalization for heart failure increased from 4.1% (over 3 years) in placebo-treated subjects to 5.7% in the pioglitazone-treated subjects. No increase in heart failure-related death was reported. Pioglitazone was associated with an increase in the risk for hypoglycemia and resulted in greater weight gain when compared with placebo treatment. Overall, rates of discontinuation were similar between groups.

PROactive is the first randomized, controlled trial to demonstrate that a specific glucose-lowering medication -- in this case, pioglitazone -- can reduce the risk for major CVD events in patients with type 2 diabetes at high risk for cardiovascular disease. Although the magnitude of effect seen with pioglitazone treatment in PROactive was less than many observers had predicted, this study represents a significant advance in our understanding of the role of glucose-lowering therapies and insulin sensitizers in the management of type 2 diabetes and CVD risk. The findings will be carefully reviewed after publication of the initial results in The Lancet. Of note, these findings will likely help practitioners as they consider the options for the treatment of type 2 diabetes. Without doubt, this study leaves a number of questions unanswered, in particular, the cost-benefit of TZD therapy and the potential for increasing both fluid retention and heart failure.

These results do suggest a role for pioglitazone in the management of CVD risk in patients with diabetes. Its benefits are significant, although they must be weighed in light of the modest additional risk for heart failure and the added cost of therapy. That said, the absolute risk reduction that is associated with pioglitazone therapy in this study was approximately 2% over 3 years. This reduction is in keeping with many of the large outcomes trials with specific CVD medications. It must be noted that pioglitazone is first and foremost a diabetes therapy -- with primary effects on glycemic control and secondary effects on lipids and vascular behavior. Subjects treated with pioglitazone in this trial achieved even better control of glucose -- perhaps as a consequence of the addition of insulin-sensitizing therapy -- than those treated without such therapy. This would likely translate not only into a modest CVD benefit but would be anticipated to reduce the risk for microvascular disease as well. In addition, these subjects achieved this improvement in control with lesser insulin use and less need for metformin therapy. These findings suggest that TZD therapy in general, and pioglitazone therapy in particular, may be essential for those attempting to achieve the most intensive levels of control -- and that pioglitazone may additionally reduce the risk for CVD events, even in those treated with "optimal" diabetes, lipid, and blood pressure therapy.

Several important limitations of PROactive should be noted. Management of cardiovascular risk factors in these subjects did not achieve current standards in a large fraction of patients. Statin use was limited to only 55% of these high-risk patients, and one can only speculate about the impact of pioglitazone if all subjects had received statins. In addition, the study's design does not allow us to ascertain which of the many metabolic improvements seen with pioglitazone therapy -- the modest improvement in glucose control, the benefits on lipids, or other factors -- may have played the most important role in limiting CVD risk. Additional research will be required to clarify the role of TZD therapy, glycemic control, and multiple risk factor intervention in the management of CVD risk in our diabetes patients

PPARs - More Than PROactive

Despite the excitement surrounding the report from the PROactive investigators, it is important to note that the EASD meeting also offered up numerous other reports on the effect of PPARs in the treatment of type 2 diabetes.
Kupfer and colleagues[12] reported that pioglitazone therapy (compared with sulfonylurea treatment) resulted in similar improvements in glycemic control but substantially greater improvements in triglycerides and HDL-C in the treatment of patients with recently diagnosed type 2 diabetes. Law and colleagues[13] reported data on nontraditional risk factors from the head-to-head trial of pioglitazone and rosiglitazone. Overall, these 2 TZDs produced similar improvement in glucose control, whereas pioglitazone treatment resulted in greater improvement in lipids. Markers of vascular inflammation and thrombosis improved with either treatment.

Other metabolic effects of PPARs were also reported. Schondorf and colleagues[14] described the impact of rosiglitazone on CVD risk factors and measures of beta-cell secretory function. Consistent with other reports, the investigators described improvements in beta-cell function and improved measures of vascular inflammation (lower levels of high-sensitivity C-reactive protein) and an increase in adiponectin.

Early combination therapy with PPARs was the subject of a report from Chou and colleagues.[15] These data support the now widely accepted practice of early combination therapy with a TZD plus metformin. Early combination therapy was also shown to result in improvements in inflammatory markers even with lesser degrees of improvement in glucose control.[16]

Belfort and colleagues[17] reported that nonalcoholic steatohepatitis improved significantly after 6 months of TZD therapy. Not only did measures of liver function improve, but early histologic improvement was also noted.

A report from Basu and colleagues[18] addressed the issue of fluid retention and weight gain seen in those treated with TZDs. The investigators reported that as much as 75% of the weight gain observed in their study was likely the consequence of an increase in total body water rather than increased fat mass. Of interest, previous reports have suggested that fluid retention accounts for approximately 2 kg of weight gain, and these results suggest that further study will be needed to clarify this issue.

Several reports addressed the issues of safety and tolerability with TZD therapy. Koro and colleagues[19] reported data on rates of common malignancies with TZD therapy. Prior studies have suggested that TZD therapy may limit the risk for some cancers (eg, breast and colon) while increasing the risk for other malignancies (eg, bladder). In this report, Dr. Koro found no increase in the relative risk for either prostate, colon, or breast cancer in patients on TZD therapy. Taken along with extensive data detailing the safety profile of the TZDs (both pioglitazone and rosiglitazone) on hepatic safety, it is clear that this class of agents remains both highly effective and generally safe.

Another report from Jacober and colleagues[20] reported comparative data on weight gain and edema from the large head-to-head trial between rosiglitazone and pioglitazone. In this study, both compounds resulted in modest weight gain (approximately 1-3 kg) over 24 weeks of therapy. In addition, rates of edema for these 2 compounds were similar, with approximately 6% to 8% of subjects developing new or worsening edema during the trial. These results are in keeping with prior reports and are the first to assess rates of edema in a prospective fashion.

Finally, Saenger and colleagues[21] reported the results of a large-scale trial of rosiglitazone therapy in children and adolescents aged 8-17 years. This unique and exciting study confirmed that TZD treatment was both effective -- resulting in A1C reductions of ~.5% -- as well as safe and well tolerated.

In addition to several basic science reports, the results of clinical trials with the so-called dual PPAR activators were also presented. The "glitazar" class of compounds, including muraglitazar and tesaglitazar, exert their therapeutic effects by activation of both PPAR gamma receptors (similar to the action of TZDs) and nuclear PPAR alpha receptors (the receptor targeted by fibrates). These compounds offer the promise of a multitude of both glycemic and lipid effects, with the hope that such therapy could be used in those with type 2 diabetes and dyslipidemia to improve both glucose control and lipid measures (particularly HDL-C and triglycerides).

Frederich and colleagues[22] reported the results from 3 large clinical trials assessing the effects of muraglitazar. In these studies, treatment with 2.5-5.0 mg of muraglitazar resulted in ~1% reductions in A1C as well as favorable effects on plasma triglycerides, HDL-C, and apolipoprotein (Apo) B concentrations. After 24 weeks of therapy (both as monotherapy or in combination with sulfonylureas or metformin), an impressive 52% to 72% of subjects treated with muraglitazar achieved A1C levels of < 7%. Similar results from a series of phase 3 clinical trials with muraglitazar were recently reported at the American Diabetes Association (ADA) Annual Scientific Sessions and reviewed by an expert committee for the US Food and Drug Administration (FDA). Muraglitazar is under review for approval in the United States for the treatment of type 2 diabetes. In addition to its salutary effects on glucose and lipids, muraglitazar does result in modest weight gain and can increase the risk for edema.

PPARs, IR, and CVD Risk: Where Are We Now?

The epidemiologic connection between IR, diabetes, and CVD is well established. The PPAR agonists as therapy for IR offer the promise of changing the natural history of diabetes and significantly reducing the risk for CVDs. The data from abstracts presented at this year's EASD meeting provide additional evidence of the multiple benefits of targeted therapy for IR. With the results of the PROactive trial, there are even stronger data to support the use of TZD therapy in diabetes patients attempting to achieve intensive control of both glucose and CVD risk.

Key Findings From EASD

• The PPAR gamma agonists (TZDs) are effective glucose-lowering therapies, and, based on data from PROactive, their role in helping patients achieve more intensive blood glucose control has been confirmed.
  
• Pioglitazone therapy can limit CVD risk over and above the risk reduction achieved with "usual care," albeit with an increased risk for excess fluid retention.
  
• TZDs are safe and well tolerated. The modest risk for fluid retention and increase in rates of hospitalization in heart failure are not associated with an increase in mortality and are associated with lesser rates of hospitalization for diabetes control.
  
• The increased risk for unmasking heart failure in those treated with TZDs requires further study. Other studies suggest that although the risk for hospitalization from heart failure may increase with TZD therapy, TZDs do have beneficial effects on cardiac function and possess the potential to limit heart failure risk over time.
  
• Dual PPAR activators are effective glucose-lowering agents and further improve lipid measures. Their role in diabetes management is an active area of clinical investigation and discussion.
  

With ever more evidence supporting the favorable effects of TZDs and PPAR activators, practitioners must consider earlier use of these agents, particularly in patients with diabetes and the metabolic syndrome at highest risk for CVD. In particular, use of these agents should be considered in any patient with clinical evidence of IR and lipid disorders (particularly low HDL levels) and in those with established CVD.

References

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2. Kendall DM, Sobel BE, Coulston AM, et al. The insulin resistance syndrome and coronary artery disease. Coron Artery Dis. 2003;14:335-348. Abstract
   
3. Cheal KL, Abassi L, Lamendola C, et al. Relationship to insulin resistance of the Adult Treatment Panel III diagnostic criteria for identification of the metabolic syndrome. Diabetes. 2004;53:1195-1200. Abstract
   
4. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689. Abstract
   
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6. Folsom AR, Szklo M, Stevens J, Liao F, Smith R, Eckfeldt JH. A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes. The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 1997;20:935-942. Abstract
   
7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. Abstract
   
8. Kendall DM, Peters Harmel AL. The metabolic syndrome, type 2 diabetes and cardiovascular disease: understanding the role of insulin resistance. Am J Manag Care. 2002;8:S635-S653. Abstract
   
9. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med. 2001;134:61-71. Abstract
   
10. Ferrannini E, Dormandy J. Results of PROactive. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece.
    
11. Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A; PROactive Study Group. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients. Diabetes Care. 2004;27:1647-1653. Abstract
    
12. Kupfer S, Perez A, Gallagher P, Zhang J. 56-week effects of pioglitazone vs glyburide on glycemic control, lipids, and LDL fractionation in subjects with recently diagnosed type 2 diabetes. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 786.
    
13. Law R, Khan M, Perez A, et al. A comparison of nontraditional atherogenic markers with pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 788.
    
14. Schondorf T, Forst T, Hamann A, et al. Impact of rosiglitazone given in addition to glimepiride treatment on cardiovascular risk markers, insulin resistance, and beta-cell function. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 787.
    
15. Chou H, Rood J, Biswas N, et al. Rosiglitazone and metformin fixed-dose combination provides superior glycemic control compared to metformin and rosiglitazone monotherapies, and was well tolerated in drug-naive type 2 diabetes patients. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 766.
    
16. Axmann C, Lubben G. Early combination therapy with pioglitazone reveals the highest benefits in patients with type 2 diabetes mellitus. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 767.
    
17. Belfort RS, Harrison S, Brown K, et al. Role of pioglitazone in patients with non-alcoholic steatohepatitis. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 770.
    
18. Basu A, Rizza RA, Joyner MJ, Jensen MD. Increased body water content is the major cause of weight gain with pioglitazone despite improved hemodynamic parameters in type 2 diabetes. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 776.
    
19. Koro CE, Barret SJ, Qizilbash N. The risk of cancer in thiazolidinedione users compared to other antidiabetic agents. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 42.
    
20. Jacober SJ, Kendall DM, Buse JB, et al. A comparison of the effects of pioglitazone versus rosiglitazone on edema and weight gain. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 774.
    
21. Saenger P, Dabiri G, Jones K, et al. Benefits of rosiglitazone in children with type 2 diabetes mellitus. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 133.
    
22. Frederich R, Mohideen P, DePril V, et al. Oral agents, clinical aspects -- attainment of HbA1c goals in type 2 diabetes patients treated with muraglitazar, a novel dual PPAR activator: experience from 3 large placebo-controlled trials. Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting; September 12-15, 2005; Athens, Greece. Abstract 38