Commentary on the Results and Clinical Implications of the PROactive Study

doi:10.2337/diacare.28.12.2965

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Commentary on the Results and Clinical Implications of the PROactive Study

Robert Rizza, MD¹, Robert Henry, MD² and Richard Kahn, PHD³

¹ Mayo Clinic & Foundation, Rochester, Minnesota
² VA San Diego HealthCare System, San Diego, California
³ American Diabetes Association, Alexandria, Virginia

Address correspondence and reprint requests to Richard Kahn, PhD, American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311. E-mail: rkahn{at}diabetes.org

Abbreviations: CVD, cardiovascular disease • PROactive, PROspective pioglitAzone Clinical Trial • TZD, thiazolidinedione

Thiazolidinediones (TZDs), or glitazones, are a relatively newclass of oral drugs that are used to treat type 2 diabetes (1–4).They lower blood glucose by targeting insulin resistance, oneof the major underlying causes of the disease. In addition totheir ability to lower blood glucose, TZDs also display a widerange of effects on lipids, blood pressure, weight, and othercardiovascular and metabolic risk factors. As with all otherdrugs, they can be associated with undesirable side effects.

By virtue of their glucose-lowering properties, all such agentswill significantly reduce the risk of the microvascular complicationsassociated with diabetes. On the other hand, no glucose-loweringagent has clearly been shown to significantly reduce macrovasculardisease.

Since TZDs, in general, have a net favorable impact on bloodlipid levels, may be associated with a reduction in blood pressure,and have positive effects on other physiological parametersassociated with vascular disease (e.g., decreasing vascularinflammation, reducing insulin resistance), they have the potentialto slow the progression of cardiovascular disease (CVD) in additionto lowering blood glucose.

Because of the above favorable actions of TZDs, the PROspectivepioglitAzone Clinical Trial (PROactive) was initiated to assessthe effects of pioglitazone (Actos; Takeda Pharmaceuticals andEli Lilly) on the secondary prevention of macrovascular eventsin type 2 diabetic patients.

Study design

PROactive was a randomized, double-blind, placebo-controlledstudy in 5,238 patients with type 2 diabetes who were managedwith diet and/or glucose-lowering medications and who had ahistory of macrovascular disease (5).

Male or female patients, aged 35–75 years, were randomizedto receive placebo or pioglitazone titrated over 2 months toits maximally approved dosage (45 mg/day). Because study participantshad preexisting CVD and diabetes of long duration (average 8years), virtually all subjects at the time of enrollment weretaking a glucose-lowering drug and other agents that help reducethe risk of CVD events.

The patients were followed for $~$ 3 years, during which the incidenceof a wide variety of macrovascular end points were tabulated.Of particular interest, however, was the incidence of all-causemortality, nonfatal myocardial infarction, and stroke.

What were the results of the PROactive study?

The addition of 45 mg pioglitazone to conventional therapy for $~$ 3 years reduced the primary end point (comprised of many adversemacrovascular outcomes) by 10% (P = 0.095) and a prespecifiedsecondary composite event rate consisting of all-cause mortality,nonfatal myocardial infarction (excluding silent myocardialinfection), and stroke by 16% (P = 0.027) compared with placebo(6). This represented an absolute risk reduction of $~$ 2% after3 years of therapy and was primarily due to reductions in strokeand nonfatal myocardial infarction. After adjustment by multivariateanalysis for entry characteristics, pioglitazone therapy wasassociated with a reduced hazard ratio of 0.84 (95% CI 0.72–0.98).

Pioglitazone treatment also was associated with a significantA1C absolute reduction of 0.5%, a relative reduction of 13%in serum triglycerides, a relative increase of 2% in LDL cholesteroland 9% in HDL cholesterol levels, and a reduction of 3 mmHgin systolic blood pressure. This resulted in a greater decreasein the LDL-to-HDL cholesterol ratio in the pioglitazone groupcompared with placebo. The proportion of patients using eithermetformin or insulin also was reduced with pioglitazone treatment.

Are the results of the PROactive study clinically meaningful?

There appeared to be a clear clinical benefit of adding pioglitazoneto type 2 diabetic patients already using most of the conventionalclasses of glucose-lowering agents. With an absolute event reductionin the secondary composite end points of $~$ 2%, one would needto treat $~$ 50 patients for 3 years to prevent one such event.Thus, in view of the substantial and well-established CVD riskreduction following cholesterol and blood pressure–loweringtherapy, emphasis should first be directed at the aggressiveuse of other conventional cardiovascular risk reduction therapy.

What adverse events were observed in the trial, and should they influence decisions regarding therapy?

Heart failure both requiring and not requiring hospitalizationwas significantly increased in the pioglitazone group (10.8%for pioglitazone vs. 7.5% for placebo, P < 0.0001), despitethe fact that individuals with New York Heart Association ClassII (i.e., symptoms with moderate activity) heart failure, orabove, were excluded from study. Since the criteria for heartfailure was not clearly defined, it remains unclear as to whetherthe frequency of this diagnosis was skewed by an increased presenceof peripheral edema in the pioglitazone group. Nevertheless,these data suggest that in the absence of extenuating circumstances,pioglitazone should not be used in individuals with a historyof clinically significant heart failure (7).

Consistent with previous studies, subjects in the pioglitazonegroup experienced greater weight gain ( $~$ 3.6 kg) than subjectsin the placebo group (0.4 kg decrease). The long-term effectsof this degree of weight gain on patient compliance and vascularrisk remains unknown. However, the fact that a reduction invascular end points was observed in the pioglitazone group despiteweight gain is reassuring. Nevertheless, it is prudent to helppatients avoid weight gain through diet and lifestyle modification.

Symptoms of hypoglycemia and hypoglycemia requiring hospitaladmission were greater in the pioglitazone arm than in the placebogroup. This observation is consistent with numerous previousstudies in which an increased frequency of hypoglycemia is observedwhenever glycemic control improves. Patients, therefore, shouldbe instructed how to recognize and treat hypoglycemia and howto modify their lifestyle and other glucose-lowering agentsso as to minimize the frequency and severity of hypoglycemicevents.

Can the results of PROactive be extrapolated to all people with diabetes?

There are many unanswered questions that preclude the assumptionthat pioglitazone would be an effective CVD intervention therapyin other patients with diabetes. First, subjects who participatedin PROactive had both diabetes and documented extensive macrovasculardisease. They were at high risk of having another vascular eventand, therefore, were an appropriate group to determine if treatmentwith pioglitazone reduced the probability of having a subsequentCVD event. The PROactive trial design, however, leaves uncertainthe question of whether people with diabetes who do not havedocumented macrovascular disease would also benefit, and ifso, whether the benefits would outweigh the risks.

Second, in excess of 98% of the subjects who participated inthe study were Caucasian. Therefore, it is not known whetherthe risks and benefits would be the same in other ethnic groups.

Third, over 95% of the participants were taking some other formof diabetes therapy. Additional studies will be required todetermine whether a comparable CVD risk reduction would be observedif pioglitazone was used as monotherapy.

Last, A1C averaged $~$ 7.8% at entry and decreased by $~$ 0.5% morein the pioglitazone than placebo group, despite efforts to optimizeglycemic control in both groups. A difference of this magnitudehas not resulted in a reduction of macrovascular events in othertrials, suggesting that the benefit of treatment relates tothe non–glucose-lowering effects of the drug that areoutlined above. It is not known whether individuals who haveoptimal glycemic control before pioglitazone therapy will havea comparable benefit.

Similar uncertainty applies if patients were first optimallytreated for any lipid and blood pressure abnormality. Of note,at the end of the study, nearly half of these high-risk subjectswere still not taking statins, and the mean systolic pressureof the population was in the hypertensive range.

Thus, the data from the PROactive study indicate that peoplewith type 2 diabetes of Caucausian heritage who have extensivemacrovascular disease, suboptimal glycemic control despite treatmentwith other diabetes therapies, suboptimal blood pressure andLDL cholesterol values, and no history of heart failure arelikely to have reduced CVD events from the addition of pioglitazoneto their current glucose-lowering therapy.

Additional studies are required to determine whether comparablebenefits and risks will be observed in people with type 2 diabetesfrom other ethnic groups, in individuals who do not have documentedmacrovascular disease, in patients whose CVD risk factors areoptimally managed with respect to current guidelines, or whenpioglitazone is used as the only glucose-lowering therapy.

Do the results of PROactive apply to all TZDs?

The TZD class of drugs are all agonists of peroxisome proliferator–activatedreceptor- ${gamma}$ , which is found in a wide variety of tissues and isknown to regulate a number of genes involved in glucose andlipid homeostasis. In addition, these drugs exert other effectsof uncertain etiology, such as improved vessel wall biologyand the mitigation of many inflammatory factors. Their glucose-loweringeffect, for which they have received drug approval, appearsto act in part by increasing insulin-stimulated glucose disposal.Despite similar mechanisms of action, and equivalent reductionsin blood glucose, currently available TZDs do not equally affectthe various risk factors that might reduce CVD morbidity andmortality (8). For example, the magnitude of triglyceride levelreduction, increase in HDL cholesterol, and effect on LDL cholesterolcan vary widely.

Because of these disparate effects on important CVD risk factors,it is premature to assume that the results of PROactive wouldhold for any other TZD or even for those drugs that are dualperoxisome proliferator–activated receptor- ${alpha}$ and - ${gamma}$ agonists.This conclusion is also supported by the fact that the designof the PROactive trial precluded the ability to ascertain whichof the many effects of pioglitazone were key to the resultsobserved. Thus, at this time, clinicians should view the resultsof this trial to be drug specific.

In addition, again because of its numerous effects on CVD riskfactors, it would be unwarranted to conclude that the insulin-sensitizingaction of pioglitazone led to the results observed. It is stillnot known whether a reduction in insulin resistance per se hasany effect on CVD mortality or morbidity. Consequently, thistrial does not provide evidence for this drug, or any otherglucose-lowering agent, as an effective treatment for the so-calledinsulin resistance (metabolic) syndrome.

Uncertainties and areas that require future research

PROactive was a carefully designed and well-executed clinicaltrial. Inclusion and exclusion criteria were carefully definedand end points appropriately specified. The fact that only twosubjects were lost to follow-up is a testimony to the dedicationand skill of the investigators. However, as with all studies,additional research questions arise, including the following.

1) To what extent do the results observed in these Caucasiansubjects apply to other ethnic groups?

2) Would similar effectsbe observed when people with underlyingvascular disease aretreated with pioglitazone alone (i.e.,monotherapy)?

3) Doespioglitazone reduce vascular events in people with diabeteswho have not had antecedent vascular events?

4) Does treatmentwith pioglitazone reduce vascular events whenblood lipid, pressure,and glucose levels are all optimallytreated?

5) Does treatmentwith pioglitazone increase, decrease, or haveno effect on thenatural history of postischemic myocardialfunction?

6) Amongthe beneficial effects of pioglitazone on CVD riskractors,which one(s) is more/less important?

7) Would comparable benefitsand risks be observed with lowerdoeses of pioglitazone (e.g.,15 or 30 mg/day).

8) Do pioglitazone or other TZDs reduceCVD or non-CVD mortalityper se?

9) Do other TZD agents providesimilar benefits and risks?

Footnotes

R.R. and R.H. have served as consultants for Takeda and GlaxoSmithKline,both of which are manufacturers of thiazolidinedione agents.

Approved by the American Diabetes Association Executive Committee,23 September 2005.

A table elsewhere in this issue shows conventional and SystèmeInternational (SI) units and conversion factors for many substances.

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