maz zone

a report by

Theodore Mazzone , MD , et al.

Chief of the Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago

Effect of Pioglitazone Compared with Glimepiride on Carotid Intima-media Thickness in Type 2 Diabetes

Patients with type 2 diabetes mellitus (DM) have a marked increase in the

risk of myocardial infarction (MI), and a substantially worse prognosis after

MI compared with patients without diabetes.13 In recent years, it has

become apparent that optimal control of blood pressure and low-density

lipoprotein cholesterol (LDL-C) level can substantially reduce excess

cardiovascular risk in patients with diabetes.46 However, even with optimal

control of these potent cardiovascular risk factors, incremental risk for

cardiovascular events remains high compared with individuals without

diabetes.23,6 New approaches are, therefore, needed to further reduce

cardiovascular risk in patients with diabetes.

Emerging evidence suggests that thiazolidinediones could be useful for

reducing cardiovascular risk. In isolated vessel-wall cells, troglitazone,

pioglitazone, and rosiglitazone have been shown to modulate gene

expression in a manner that would be predicted to be atheroprotective in

vivo.78 In humans, these agents have been shown to have beneficial effects

on systemic inflammatory and coagulation markers, lipoprotein profile, and

endothelial cell function.912 Some of these beneficial effects may be

independent of effects on glycemia.1315 In animal models of atherosclerosis,

thiazolidinediones have been shown to reduce atherosclerotic plaque area

independent of changes in glycemia or lipid profile.1617

When investigating the usefulness of therapies for preventing cardiovascular

events, several surrogate end-points for estimating future risk of such events

have been evaluated. The measurement of carotid intima-media thickness

(CIMT) is among the best validated of these surrogate end-points.18 CIMT

has been shown to highly correlate with risk of future cardiovascular events,

and changes in CIMT over time have additional predictive value.1819 Statins,

established agents for reducing risk of cardiovascular disease events, have

been shown to reduce progression of CIMT.18,20

There have been recent reports examining the effect of thiazolidinediones

on CIMT in diabetes.13,21-24 Minamikawa et al.23 reported that troglitazone

compared with no added treatment reduced CIMT at three and six months

in 135 Japanese patients. Langenfeld et al.22 compared pioglitazone with

glimepiride in 173 white German participants and reported a reduction in

CIMT at 24 weeks. The participants had a baseline systolic blood pressure of

approximately 148mmHg and an LDL-C level of approximately 136mg/dl

(3.5mmol/l). In spite of this elevated LDL-C level, statin use was less than

20% at the start of the study. Hodis et al.24 recently reported results from

299 patients with type 2 DM. This cohort was more than 66% female and

more than 86% Hispanic-American and was randomized to receive

troglitazone or placebo for two years. Overall, the change in CIMT was not

different between the two treatment groups, although a beneficial effect of

troglitazone was observed in the subgroup with a baseline CIMT of 0.8mm

or greater. Because of important issues related to small cohort size, short

duration of treatment, homogeneity of study population with respect to

race/ethnicity, the presence of uncontrolled cardiovascular risk factors, and

inconsistent results, there remains an important question regarding the

effect of thiazolidinediones on CIMT in type 2 DM.

Below are the findings of a long-term randomized and comparator-

controlled clinical trial conducted in patients with type 2 DM recruited

from an ethnically/racially diverse population of a large US metropolitan

area. The study compared the effect of pioglitazone with that of

glimepiride on progression of CIMT. Glimepiride was chosen as a

comparator because a placebo control could not be ethically justified in

terms of maintaining adequate glycemic control. In addition, glimepiride

represents a class of drugs that is commonly used to treat diabetes in the

US, and its mechanism of action is distinct from that of pioglitazone.

Study Discussion and Comment

In this randomized trial of 462 patients with type 2 DM, we found that,

compared with glimepiride, pioglitazone reduced CIMT progression, a

validated surrogate end-point for coronary artery disease and cardiovascular

risk.1819 The CHICAGO trial was conducted in a single geographical region,

allowing measurement of CIMT to be performed at a single location by a single

sonographer. The analysis used automated digital edge-detection technology

and included multiple measurements in each carotid artery segment. Our study

population was recruited from a racially and ethnically diverse population of a

large US city and generally reflects the diversity of the type 2 DM population in

the US. Our results demonstrate reduction of CIMT progression with

pioglitazone treatment in a cohort with a better level of management of

cardiovascular risk factors (i.e., a higher rate of statin use, LDL-C levels near 100

mg/dl [2.6mmol/l], and near-optimal blood pressure control) compared with

previously reported cohorts.22 Our study also included repeated measurements

up to 72 weeks, beyond the three- to six-month treatment period in previous

trials using pioglitazone.13,2122 A pre-specified subgroup analysis based on age,

sex, systolic blood pressure, duration of type 2 DM, body mass index,

glycosylated hemoglocin (HbA1c) value, and statin use showed a uniform

Disease Risk Management

25 T O U C H B R I E F I N G S 2 0 0 7

Theodore Mazzone, MD, is Professor of Medicine and Pharmacology and Chief of the Sectionof Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois atChicago. His clinical interests include insulin resistance, lipid disorders, and multiple risk factordiabetes. His key research areas include the mechanism and prevention of artherosclerosis,prevention of macrovascular complications of diabetes, and adipose tissue lipid metabolism inobesity. Dr Mazzone attended Northwestern University and completed his residency at UCLA.

Mazzone_USCardio.qxp 2/7/07 12:28 pm Page 25


26 U S C A R D I O V A S C U L A R D I S E A S E 2 0 0 7

beneficial effect of pioglitazone treatment.

Systolic blood pressure was reduced by a small amount in both treatment

groups. This effect was slightly larger in the pioglitazone group, but

treatment differences did not reach statistical significance. Pre-specified

cardiovascular end-points were adjudicated in a double-blinded fashion by

an independent panel and more of these events, mostly related to coronary

revascularization, occurred in the glimepiride group. There was one case of

new congestive heart failure with pioglitazone therapy, while hypoglycemia

was slightly more common with glimepiride. As expected, edema and

weight gain were more common in the pioglitazone group. CIMT has been

extensively evaluated as a surrogate marker of atherosclerosis and

cardiovascular risk.1819 It has recently been suggested that changes in

maximum CIMT may be preferred for measuring treatment-related changes

in carotid atherosclerosis.25 Our results demonstrate beneficial effects of

pioglitazone on progression for both mean and maximal CIMT values.

In patients with type 2 DM, measurement of CIMT significantly improves

prediction of cardiovascular disease risk compared with the Framingham

Risk Score.26 It has also been shown that changes in CIMT over time

correlate with future cardiovascular event rates.1819 Diabetes, which confers

increased risk of cardiovascular disease, also accelerates CIMT progression.27

However, CIMT progression rates vary widely in patients with diabetes, from

0.083mm over six months to 0.007mm over onw year.27,28 In a recent review

of 11 CIMT intervention trials in diabetes,29 the mean CIMT progression rate

in the control groups was 0.034mm per year, but varied considerably

between trials based on level of control of cardiovascular risk factors. The

low rate of progession in the control group of the current study likely

reflects the control of systolic blood pressure and LDL-C level.

The beneficial effect of pioglitazone on CIMT in patients with type 2 DM is

consistent with results of the recently reported PROactive (Prospective

Pioglitazone Clinical Trial in Macrovascular Events) study.30 This trial

randomized more than 5,000 patients with type 2 DM who had evidence of

macrovascular disease to receive pioglitazone or placebo in addition to

existing therapy. While treatment with pioglitazone did not significantly

reduce the risk of the composite primary end-point (which included death

from any cause, nonfatal MI, stroke, acute coronary syndrome, leg

amputation, coronary revascularization, or leg revascularization), it did

significantly reduce by 16% the risk of the main secondary end-point (a

composite of all-cause mortality, MI, or stroke).

Several potential mechanisms can be considered for a beneficial effect of

pioglitazone on atherosclerosis. Treatment with thiazolidinediones has been

shown to modify nontraditional markers of cardiac risk such as circulating

inflammatory and coagulation markers and to improve endothelial-cell

function.912,3132 Thiazolidinedione treatment can also positively modify blood

pressure, glycemia, and lipid levels.912 In the current study, blood pressure

changes were not significantly different between the pioglitazone and

glimepiride groups. HbA1c values were reduced more in the pioglitazone group

compared with the glimepiride group (by 0.32% at 72 weeks). However, it is

noteworthy that the treatment advantage for pioglitazone on HbA1c values in

this study did not become significant until week 48. In prior studies, treatment

with pioglitazone has been shown to have a substantial benefit on diabetic

dyslipidemia, including increasing HDL-C levels and reducing triglycerides

levels.12 Both of these effects were observed in our study and could have

contributed to improvement in CIMT. Finally, it also remains possible that

thiazolidinediones can have a directly beneficial effect on the vessel wall.1617

Our study has several limitations. First, it was not powered to detect a

difference in cardiovascular end-points and, therefore, does not establish

that treatment with pioglitazone compared with glimepiride will reduce

these end-points in patients with type 2 DM. Because we used glimepiride

StudyIn Brief

Objective

To evaluate the effect of pioglitazone versus glimepiride on changes

in CIMT of the common carotid artery in patients with type 2 DM.

Design, Setting, and Participants

Randomized, double-blind, comparator-controlled, multicenter trial in

patients with type 2 DM conducted at 28 clinical sites in the

multiracial/ethnic Chicago metropolitan area between October 2003

and May 2006. The treatment period was 72 weeks (one-week follow-

up). CIMT images were captured by a single ultrasonographer at one

center and read by a single treatment-blinded reader using automated

edge-detection technology. Participants were 462 adults (mean age, 60

[standard deviation, SD, 8.1] years; mean body mass index, 32 [SD, 5.1])

with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean HbA1c value,

7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet

and exercise, sulfonylurea, metformin, insulin, or a combination thereof.

Interventions

Pioglitazone hydrochloride (1545mg/d) or glimepiride (14mg/d) as

an active comparator.

Main Outcome Measure

Absolute change from baseline to final visit in mean posterior-wall

CIMT of the left and right common carotid arteries.

Results

Mean change in CIMT was lower with pioglitazone versus glimepiride

at all time-points (weeks 24, 48, 72). At week 72, the primary end-

point of progression of mean CIMT was less with pioglitazone versus

glimepiride (-0.001mm versus +0.012mm, respectively; difference,

-0.013mm; 95% confidence interval, -0.024 to -0.002; p=0.02).

Pioglitazone also slowed progression of maximum CIMT compared

with glimepiride (0.002mm versus 0.026mm, respectively, at 72

weeks; difference, -0.024mm; 95% confidence interval, -0.042 to

-0.006; p=0.008). The beneficial effect of pioglitazone on mean CIMT

was similar across pre-specified subgroups based on age, sex, systolic

blood pressure, duration of DM, body mass index, HbA1c value, and

statin use.

Conclusion

Over an 18-month treatment period in patients with type 2 DM,

pioglitazone slowed progression of CIMT compared with glimepiride.

For full results and statistical analysis, please view original paper

(JAMA, 2006;296) available at: doi:10.1001/jama.296.21.joc60158


Please see adjacent Brief Summary of Prescribing Information, including boxedwarning regarding lactic acidosis. For more information and Complete PrescribingInformation, please visit us at www.actos.com.

Two agents.One tablet.One co-pay.

Takeda_ad.qxp 2/7/07 11:29 am Page 27

ACTOPLUS MET(pioglitazone hydrochloride and metformin hydrochloride) tabletsBrief Summary of Prescribing Information. Please see packageinsert for Complete Prescribing Information.INDICATIONS AND USAGEACTOPLUS MET is indicated as an adjunct to diet and exercise to improveglycemic control in patients with type 2 diabetes who are already treated with acombination of pioglitazone and metformin or whose diabetes is not adequatelycontrolled with metformin alone, or for those patients who have initially respondedto pioglitazone alone and require additional glycemic control.Management of type2 diabetes should also include nutritional counseling, weight reduction as needed,and exercise.These efforts are important not only in the primary treatment of type2 diabetes, but also to maintain the efficacy of drug therapy.CONTRAINDICATIONSACTOPLUS MET is contraindicated in patients with:

1. Renal disease or renal dysfunction (e.g., as suggested by serum creatininelevels 1.5 mg/dL [males], 1.4 mg/dL [females], or abnormal creatinineclearance) which may also result from conditions such as cardiovascularcollapse (shock), acute myocardial infarction, and septicemia (see WARNINGS, Metformin hydrochloride and PRECAUTIONS, General: Metformin hydrochloride).

2. Known hypersensitivity to pioglitazone, metformin or any other componentof ACTOPLUS MET.

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

ACTOPLUS MET should be temporarily discontinued in patients undergoingradiologic studies involving intravascular administration of iodinated contrastmaterials, because use of such products may result in acute alteration ofrenal function (see PRECAUTIONS, General: Metformin hydrochloride).WARNINGSMetformin hydrochlorideLactic Acidosis: Lactic acidosis is a rare, but serious, metabolic compli-cation that can occur due to metformin accumulation during treatmentwith ACTOPLUS MET (pioglitazone hydrochloride and metforminhydrochloride) tablets; when it occurs, it is fatal in ~50% of cases. Lacticacidosis may also occur in association with a number of pathophysiologicconditions, including diabetes mellitus, and whenever there is significanttissue hypoperfusion and hypoxemia. Lactic acidosis is characterized byelevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolytedisturbances with an increased anion gap, and an increasedlactate/pyruvate ratio. When metformin is implicated as the cause oflactic acidosis, metformin plasma levels >5 g/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metforminhydrochloride is very low (~0.03 cases/1000 patient-years, with ~0.015fatal cases/1000 patient-years). In >20,000 patient-years exposure to met-formin in clinical trials, there were no reports of lactic acidosis. Reportedcases have occurred primarily in diabetic patients with significant renalinsufficiency, including both intrinsic renal disease and renal hypoperfusion,often in the setting of multiple concomitant medical/surgical problems andmultiple concomitant medications. Patients with congestive heart failure(CHF) requiring pharmacologic management, in particular those withunstable or acute CHF who are at risk of hypoperfusion and hypoxemia,areat increased risk of lactic acidosis.The risk of lactic acidosis increases withthe degree of renal dysfunction and the patients age. The risk of lacticacidosis may, therefore,be significantly decreased by regular monitoring ofrenal function in patients taking metformin and by use of the minimumeffective dose of metformin. In particular, treatment of the elderly should beaccompanied by careful monitoring of renal function. Metformin treatmentshould not be initiated in patients 80 years of age unless measurementof creatinine clearance demonstrates that renal function is not reduced,as these patients are more susceptible to developing lactic acidosis. Inaddition, metformin should be promptly withheld in the presence of anycondition associated with hypoxemia, dehydration, or sepsis. Becauseimpaired hepatic function may significantly limit the ability to clear lactate,metformin should generally be avoided in patients with clinical orlaboratory evidence of hepatic disease. Patients should be cautionedagainst excessive alcohol intake, either acute or chronic, when taking met-formin, since alcohol potentiates the effects of metformin hydrochloride onlactate metabolism. In addition, metformin should be temporarilydiscontinued prior to any intravascular radiocontrast study and for anysurgical procedure (see PRECAUTIONS, General: Metformin hydrochloride).

The onset of lactic acidosis often is subtle, and accompanied only bynonspecific symptoms such as malaise, myalgias, respiratory distress,increasing somnolence, and nonspecific abdominal distress. Theremay be associated hypothermia, hypotension, and resistant brady-arrhythmias with more marked acidosis. The patient and the patientsphysician must be aware of the possible importance of such symptomsand the patient should be instructed to notify the physician immediatelyif they occur (see PRECAUTIONS, General: Metformin hydrochloride).Metformin should be withdrawn until the situation is clarified. Serumelectrolytes, ketones, blood glucose, and, if indicated, blood pH, lactatelevels, and even blood metformin levels may be useful. Once a patientis stabilized on any dose level of metformin, gastrointestinal symptoms,which are common during initiation of therapy, are unlikely to be drugrelated. Later occurrence of gastrointestinal symptoms could be due tolactic acidosis or other serious disease.

Levels of fasting venous plasma lactate > the upper limit of normal(ULN) but 4700 patients withtype 2 diabetes received pioglitazone. There was no evidence of drug-inducedhepatotoxicity or elevation of alanine aminotransferase (ALT) levels in the clinicalstudies. During pre-approval placebo-controlled clinical trials in the U.S., a totalof 4/1526 (0.26%) patients treated with pioglitazone and 2/793 (0.25%) place-bo-treated patients had ALT values 3x the ULN.The ALT elevations in patientstreated with pioglitazone were reversible and were not clearly related to therapywith pioglitazone. In postmarketing experience with pioglitazone, reports ofhepatitis and of hepatic enzyme elevations to 3x the ULN have been received.Very rarely, these reports have involved hepatic failure with and without fataloutcome, although causality has not been established.

Pending the availability of the results of additional large, long-term controlledclinical trials and additional postmarketing safety data on pioglitazone, it isrecommended that patients treated with ACTOPLUS MET undergo periodicmonitoring of liver enzymes.

Serum ALT levels should be evaluated prior to the initiation of therapy withACTOPLUS MET in all patients and periodically thereafter per the clinical judg-ment of the health care professional. Liver function tests should also beobtained for patients if symptoms suggestive of hepatic dysfunction occur,e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Thedecision whether to continue the patient on therapy with ACTOPLUS METshould be guided by clinical judgment pending laboratory evaluations. Ifjaundice is observed, drug therapy should be discontinued.

Therapy with ACTOPLUS MET should not be initiated if the patient exhibitsclinical evidence of active liver disease or the ALT levels are >2.5x the ULN.Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5x the ULN)at baseline or any time during therapy with ACTOPLUS MET should be evaluatedto determine the cause of the liver enzyme elevation. Initiation or continuationof therapy with ACTOPLUS MET in patients with mildly elevated liver enzymesshould proceed with caution and include appropriate clinical follow-up whichmay include more frequent liver enzyme monitoring. If serum transaminaselevels are increased (ALT >2.5x the ULN), liver function tests should beevaluated more frequently until the levels return to normal or pretreatmentvalues. If ALT levels exceed 3x the ULN, the test should be repeated as soonas possible. If ALT levels remain >3x the ULN or if the patient is jaundiced,ACTOPLUS MET therapy should be discontinued.Macular Edema: Macular edema has been reported in post-marketing experiencein diabetic patients who were taking pioglitazone or another TZD. Some patientspresented with blurred vision or decreased visual acuity, but some patients appearto have been diagnosed on routine ophthalmologic examination. Some patientshad peripheral edema at the time macular edema was diagnosed. Some patientshad improvement in their macular edema after discontinuation of their TZD. It isunknown whether there is a causal relationship between pioglitazone andmacular edema. Patients with diabetes should have regular eye exams by anophthalmologist, per the Standards of Care of the American Diabetes Association.Additionally, any diabetic who reports any kind of visual symptom should bepromptly referred to an ophthalmologist, regardless of the patients underlyingmedications or other physical findings (see ADVERSE REACTIONS).General: Metformin hydrochlorideMonitoring of renal function: Metformin is known to be substantially excreted bythe kidney, and the risk of metformin accumulation and lactic acidosis increaseswith the degree of impairment of renal function. Thus, patients with serumcreatinine levels above the ULN for their age should not receive ACTOPLUS MET.In patients with advanced age, ACTOPLUS MET should be carefully titrated toestablish the minimum dose for adequate glycemic effect, because aging isassociated with reduced renal function. In elderly patients, particularly those80 years of age, renal function should be monitored regularly and, generally,ACTOPLUS MET should not be titrated to the maximum dose of the metformincomponent (see WARNINGS, Metformin hydrochloride).

Before initiation of therapy with ACTOPLUS MET and at least annually there-after, renal function should be assessed and verified as normal. In patients inwhom development of renal dysfunction is anticipated, renal function shouldbe assessed more frequently and ACTOPLUS MET discontinued if evidence ofrenal impairment is present.Use of concomitant medications that may affect renal function or met-formin disposition: Concomitant medication(s) that may affect renal func-tion or result in significant hemodynamic change or may interfere with thedisposition of metformin, such as cationic drugs that are eliminated byrenal tubular secretion (see PRECAUTIONS, Drug Interactions, Metforminhydrochloride), should be used with caution.Radiologic studies involving the use of intravascular iodinated contrast materials(for example, intravenous urogram, intravenous cholangiography, angiography,and computed tomography (CT) scans with intravascular contrast materials):Intravascular contrast studies with iodinated materials can lead to acute alterationof renal function and have been associated with lactic acidosis in patientsreceiving metformin (see CONTRAINDICATIONS). Therefore, in patients inwhom any such study is planned, ACTOPLUS MET should be temporarilydiscontinued at the time of or prior to the procedure, and withheld for 48hours subsequent to the procedure and reinstituted only after renal functionhas been re-evaluated and found to be normal.Hypoxic states: Cardiovascular collapse (shock) from whatever cause,acute CHF, acute myocardial infarction and other conditions characterizedby hypoxemia have been associated with lactic acidosis and may alsocause prerenal azotemia. When such events occur in patients receivingACTOPLUS MET therapy, the drug should be promptly discontinued.Surgical procedures: Use of ACTOPLUS MET should be temporarily suspendedfor any surgical procedure (except minor procedures not associated with restrictedintake of food and fluids) and should not be restarted until the patients oral intakehas resumed and renal function has been evaluated as normal.Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactatemetabolism. Patients, therefore, should be warned against excessive alcoholintake, acute or chronic, while receiving ACTOPLUS MET.Impaired hepatic function: Since impaired hepatic function has been associatedwith some cases of lactic acidosis, ACTOPLUS MET should generally be avoidedin patients with clinical or laboratory evidence of hepatic disease.Vitamin B12 levels: In controlled clinical trials of metformin at 29 weeksduration, a decrease to subnormal levels of previously normal serum vitaminB12 levels, without clinical manifestations, was observed in ~7% ofpatients. Such decrease, possibly due to interference with B12 absorptionfrom the B12-intrinsic factor complex, is, however, very rarely associatedwith anemia and appears to be rapidly reversible with discontinuation ofmetformin or vitamin B12 supplementation. Measurement of hematologicparameters on an annual basis is advised in patients on ACTOPLUS METand any apparent abnormalities should be appropriately investigated andmanaged (see PRECAUTIONS, General: Metformin hydrochloride andLaboratory Tests). Certain individuals (those with inadequate vitamin B12 orcalcium intake or absorption) appear to be predisposed to developing subnormalvitamin B12 levels. In these patients, routine serum vitamin B12 measurements attwo- to three-year intervals may be useful.Change in clinical status of patients with previously controlled type 2 diabetes:A patient with type 2 diabetes previously well-controlled on ACTOPLUS METwho develops laboratory abnormalities or clinical illness (especially vague andpoorly defined illness) should be evaluated promptly for evidence of ketoaci-dosis or lactic acidosis. Evaluation should include serum electrolytes andketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and met-formin levels. If acidosis of either form occurs, ACTOPLUS MET must bestopped immediately and other appropriate corrective measures initiated (seeWARNINGS, Metformin hydrochloride).Hypoglycemia: Hypoglycemia does not occur in patients receiving met-formin alone under usual circumstances of use, but could occur whencaloric intake is deficient, when strenuous exercise is not compensated bycaloric supplementation, or during concomitant use with hypoglycemicagents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated ormalnourished patients and those with adrenal or pituitary insufficiency oralcohol intoxication are particularly susceptible to hypoglycemic effects.Hypoglycemia may be difficult to recognize in the elderly and in peoplewho are taking beta-adrenergic blocking drugs.Loss of control of blood glucose: When a patient stabilized on any diabet-ic regimen is exposed to stress such as fever, trauma, infection, or surgery,a temporary loss of glycemic control may occur. At such times, it may benecessary to withhold ACTOPLUS MET and temporarily administer insulin.ACTOPLUS MET may be reinstituted after the acute episode is resolved.Laboratory TestsFPG and A1C measurements should be performed periodically to monitorglycemic control and therapeutic response to ACTOPLUS MET.

Liver enzyme monitoring is recommended prior to initiation of therapy withACTOPLUS MET in all patients and periodically thereafter per the clinical judg-

Table 1. Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with Pioglitazone

Note: Trial durations of 16 to 24 weeks

Insulin

Metformin

Sulfonylurea

Monotherapy

CombinationTherapy

-0.5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3)n=187 n=183 n=528 n=333

-1.4 (-3.2/0.3) 0.9 (-0.3/3.2) 1.8 (-0.9/5.0)n=160 n=567 n=407

0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8)n=182 n=190 n=522 n=338

Control pioglitazone pioglitazone pioglitazoneGroup 15 mg 30 mg 45 mgMedian Median Median Median

(25th/75th (25th/75th (25th/75th (25th/75thpercentile) percentile) percentile) percentile)

-1.4 (-2.7/0.0) 0.9 (-0.5/3.4) 1.0 (-0.9/3.4) 2.6 (0.2/5.4)n=256 n=188

N/A

n=79 n=79


ment of the health care professional (see PRECAUTIONS, General: Pioglitazonehydrochloride and ADVERSE REACTIONS, Serum Transaminase Levels).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglo-bin/hematocrit and red blood cell indices) and renal function (serum creatinine)should be performed, at least on an annual basis. While megaloblastic anemiahas rarely been seen with metformin therapy, if this is suspected, vitamin B12deficiency should be excluded.Information for Patients Patients should be instructed regarding the importance of adhering to dietaryinstructions, a regular exercise program, and regular testing of blood glucoseand A1C. During periods of stress such as fever, trauma, infection, or surgery,medication requirements may change and patients should be reminded toseek medical advice promptly.

The risks of lactic acidosis, its symptoms and conditions that predispose toits development, as noted in the WARNINGS, Metformin hydrochloride and PRE-CAUTIONS, General: Metformin hydrochloride sections, should be explained topatients. Patients should be advised to discontinue ACTOPLUS MET immediatelyand to promptly notify their health care professional if unexplained hyperventilation,myalgia, malaise, unusual somnolence or other nonspecific symptoms occur.Gastrointestinal symptoms are common during initiation of metformin treatmentand may occur during initiation of ACTOPLUS MET therapy; however, patientsshould consult with their physician if they develop unexplained symptoms.Although gastrointestinal symptoms that occur after stabilization are unlikely tobe drug related, such an occurrence of symptoms should be evaluated todetermine if it may be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake, either acuteor chronic, while receiving ACTOPLUS MET.

Patients who experience an unusually rapid increase in weight or edema orwho develop shortness of breath or other symptoms of heart failure while onACTOPLUS MET should immediately report these symptoms to their physician.

Patients should be told that blood tests for liver function will be performedprior to the start of therapy and periodically thereafter per the clinical judgmentof the health care professional. Patients should be told to seek immediatemedical advice for unexplained nausea, vomiting, abdominal pain, fatigue,anorexia, or dark urine.

Patients should be informed about the importance of regular testing ofrenal function and hematologic parameters when receiving treatment withACTOPLUS MET.

Therapy with a TZD, which is the active pioglitazone component of theACTOPLUS MET tablet, may result in ovulation in some premenopausalanovulatory women. As a result, these patients may be at an increased risk forpregnancy while taking ACTOPLUS MET. Thus, adequate contraception in pre-menopausal women should be recommended.This possible effect has not beeninvestigated in clinical studies so the frequency of this occurrence is not known.

Combination antihyperglycemic therapy may cause hypoglycemia. When initi-ating ACTOPLUS MET, the risks of hypoglycemia, its symptoms and treatment,andconditions that predispose to its development should be explained to patients.

Patients should be told to take ACTOPLUS MET as prescribed and instructedthat any change in dosing should only be done if directed by their physician.Drug InteractionsPioglitazone hydrochlorideIn vivo drug-drug interaction studies have suggested that pioglitazone may bea weak inducer of CYP450 isoform 3A4 substrate. An enzyme inhibitor ofCYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazoneand an enzyme inducer of CYP2C8 (such as rifampin) may significantlydecrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer ofCYP2C8 is started or stopped during treatment with pioglitazone, changes indiabetes treatment may be needed based on clinical response.Metformin hydrochlorideFurosemide: A single-dose, metformin-furosemide drug interaction study inhealthy subjects demonstrated that pharmacokinetic parameters of bothcompounds were affected by co-administration. Furosemide increased themetformin plasma and blood Cmax by 22% and blood AUC by 15%, withoutany significant change in metformin renal clearance. When administered withmetformin, the Cmax and AUC of furosemide were 31% and 12% smaller,respectively, than when administered alone and the terminal half-life wasdecreased by 32%, without any significant change in furosemide renalclearance. No information is available about the interaction of metformin andfurosemide when co-administered chronically.Nifedipine: A single-dose, metformin-nifedipine drug interaction study innormal healthy volunteers demonstrated that co-administration of nifedipineincreased plasma metformin Cmax and AUC by 20% and 9%, respectively, andincreased the amount excreted in the urine. Tmax and half-life were unaffected.Nifedipine appears to enhance the absorption of metformin. Metformin hadminimal effects on nifedipine.Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, pro-cainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, andvancomycin) that are eliminated by renal tubular secretion theoreticallyhave the potential for interaction with metformin by competing for commonrenal tubular transport systems. Such interaction between metformin and oralcimetidine has been observed in normal healthy volunteers in both single-and multiple-dose, metformin-cimetidine drug interaction studies with a 60%increase in peak metformin plasma and whole blood concentrations and a40% increase in plasma and whole blood metformin AUC. There was nochange in elimination half-life in the single-dose study. Metformin had noeffect on cimetidine pharmacokinetics. Although such interactions remaintheoretical (except for cimetidine), careful patient monitoring and doseadjustment of ACTOPLUS MET and/or the interfering drug is recommendedin patients who are taking cationic medications that are excreted via theproximal renal tubular secretory system.Other: Certain drugs tend to produce hyperglycemia and may lead to loss ofglycemic control.These drugs include thiazides and other diuretics, corticosteroids,phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.When such drugs are administered to a patient receiving ACTOPLUS MET, thepatient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranololand metformin and ibuprofen were not affected when co-administered insingle-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is therefore less likelyto interact with highly protein-bound drugs such as salicylates, sulfonamides,chloramphenicol and probenecid.

Carcinogenesis, Mutagenesis, Impairment of Fertility ACTOPLUS METNo animal studies have been conducted with ACTOPLUS MET. The followingdata are based on findings in studies performed with pioglitazone or met-formin individually.Pioglitazone hydrochlorideA two-year carcinogenicity study was conducted in male and female rats atoral doses 63 mg/kg (~14x the maximum recommended human oral doseof 45 mg based on mg/m2). Drug-induced tumors were not observed in anyorgan except for the urinary bladder. Benign and/or malignant transitional cellneoplasms were observed in male rats at 4 mg/kg/day (~ the maximum rec-

ommended human oral dose based on mg/m2). A two-year carcinogenicitystudy was conducted in male and female mice at oral doses 100mg/kg/day (~11x the maximum recommended human oral dose based on mg/m2). Nodrug-induced tumors were observed in any organ.

During prospective evaluation of urinary cytology involving >1800 patientsreceiving pioglitazone in clinical trials one year in duration, no new cases ofbladder tumors were identified. In two 3-year studies in which pioglitazonewas compared to placebo or glyburide, there were 16/3656 (0.44%) reportsof bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%)in patients not taking pioglitazone. After excluding patients in whom exposureto study drug was < one year at the time of diagnosis of bladder cancer, therewere six (0.16%) cases on pioglitazone and two (0.05%) on placebo.

Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies,including the Ames bacterial assay, a mammalian cell forward gene mutationassay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHLcells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oraldoses 40 mg/kg pioglitazone HCl daily prior to and throughout mating and ges-tation (~9x the maximum recommended human oral dose based on mg/m2).Metformin hydrochlorideLong-term carcinogenicity studies have been performed in rats (dosing durationof 104 weeks) and mice (dosing duration of 91 weeks) at doses 900 mg/kg/dayand 1500 mg/kg/day, respectively. These doses are both ~4x a human dailydose of 2000 mg of the metformin component of ACTOPLUS MET based onbody surface area comparisons. No evidence of carcinogenicity with met-formin was found in either male or female mice. Similarly, there was notumorigenic potential observed with metformin in male rats. There was, how-ever, an increased incidence of benign stromal uterine polyps in female ratstreated with 900 mg/kg/day.

There was no evidence of mutagenic potential of metformin in the followingin vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lym-phoma cells), or chromosomal aberrations test (human lymphocytes). Resultsin the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin whenadministered at doses as high as 600 mg/kg/day, which is ~3x the maxi-mum recommended human daily dose of the metformin component ofACTOPLUS MET based on body surface area comparisons.

Animal ToxicologyPioglitazone hydrochlorideHeart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg)and dogs (3 mg/kg) treated orally with the pioglitazone HCl component ofACTOPLUS MET (~11, 1, and 2x the maximum recommended human oraldose for mice, rats, and dogs, respectively, based on mg/m2). In a one-yearrat study, drug-related early death due to apparent heart dysfunction occurredat an oral dose of 160 mg/kg/day (~35x the maximum recommended humanoral dose based on mg/m2). Heart enlargement was seen in a 13-weekstudy in monkeys at oral doses of 8.9 mg/kg and above (~4x the maximumrecommended human oral dose based on mg/m2), but not in a 52-weekstudy at oral doses up to 32 mg/kg (~13x the maximum recommendedhuman oral dose based on mg/m2).

Pregnancy: Pregnancy Category CACTOPLUS METBecause current information strongly suggests that abnormal blood glucoselevels during pregnancy are associated with a higher incidence of congenitalanomalies, as well as increased neonatal morbidity and mortality, most expertsrecommend that insulin be used during pregnancy to maintain blood glucoselevels as close to normal as possible.ACTOPLUS MET should not be used duringpregnancy unless the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women withACTOPLUS MET or its individual components. No animal studies have been con-ducted with the combined products in ACTOPLUS MET. The following data arebased on findings in studies performed with pioglitazone or metformin individually.Pioglitazone hydrochloridePioglitazone was not teratogenic in rats at oral doses 80 mg/kg or in rabbitsgiven 160 mg/kg during organogenesis (~17 and 40x the maximum rec-ommended human oral dose based on mg/m2, respectively). Delayed par-turition and embryotoxicity (as evidenced by increased postimplantationlosses, delayed development and reduced fetal weights) were observed inrats at oral doses of 40 mg/kg/day (~10x the maximum recommendedhuman oral dose based on mg/m2). No functional or behavioral toxicitywas observed in offspring of rats. In rabbits, embryotoxicity was observedat an oral dose of 160 mg/kg (~40x the maximum recommended humanoral dose based on mg/m2). Delayed postnatal development, attributed todecreased body weight, was observed in offspring of rats at oral doses of10 mg/kg during late gestation and lactation periods (~2x the maximumrecommended human oral dose based on mg/m2).Metformin hydrochlorideMetformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day.This represents an exposure of about two and 6x a human daily dose of2000 mg based on body surface area comparisons for rats and rabbits,respectively. Determination of fetal concentrations demonstrated a partialplacental barrier to metformin.Nursing Mothers No studies have been conducted with the combined components of ACTOPLUS MET.In studies performed with the individual components, both pioglitazone andmetformin are secreted in the milk of lactating rats. It is not known whetherpioglitazone and/or metformin is secreted in human milk. Because many drugsare excreted in human milk, ACTOPLUS MET should not be administered to abreastfeeding woman. If ACTOPLUS MET is discontinued, and if diet alone isinadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use Safety and effectiveness of ACTOPLUS MET in pediatric patients have notbeen established.

Elderly Use Pioglitazone hydrochloride~500 patients in placebo-controlled clinical trials of pioglitazone were 65.No significant differences in effectiveness and safety were observed betweenthese patients and younger patients.Metformin hydrochlorideControlled clinical studies of metformin did not include sufficient numbers ofelderly patients to determine whether they respond differently from youngerpatients, although other reported clinical experience has not identified differ-ences in responses between the elderly and young patients. Metformin isknown to be substantially excreted by the kidney and because the risk of seriousadverse reactions to the drug is greater in patients with impaired renalfunction, ACTOPLUS MET should only be used in patients with normal renalfunction (see CONTRAINDICATIONS, WARNINGS, Metformin hydrochloride).Because aging is associated with reduced renal function, ACTOPLUS METshould be used with caution as age increases. Care should be taken in doseselection and should be based on careful and regular monitoring of renalfunction. Generally, elderly patients should not be titrated to the maximumdose of ACTOPLUS MET (see WARNINGS, Metformin hydrochloride).

ADVERSE REACTIONS The most common adverse events reported in 5% of patients in the con-trolled 16-week clinical trial between placebo plus metformin and pioglitazone30 mg plus metformin were upper respiratory tract infection (15.6% and15.5%), diarrhea (6.3% and 4.8%), combined edema/peripheral edema (2.5%and 6.0%) and headache (1.9% and 6.0%), respectively.

The incidence and type of adverse events reported in 5% of patients inany combined treatment group from the 24-week study comparing pioglitazone30 mg plus metformin and pioglitazone 45 mg plus metformin are shown inTable 2; the rate of adverse events resulting in study discontinuation betweenthe two treatment groups was 7.8% and 7.7%, respectively.

Most clinical adverse events were similar between groups treated withpioglitazone in combination with metformin and those treated with pioglitazonemonotherapy. Other adverse events reported in 5% of patients in controlledclinical trials between placebo and pioglitazone monotherapy included myalgia(2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggra-vated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.

In U.S. double-blind studies, anemia was reported in 2% of patients treatedwith pioglitazone plus metformin (see PRECAUTIONS, General: Pioglitazonehydrochloride). In monotherapy studies, edema was reported for 4.8% (withdoses from 7.5 mg to 45 mg) of patients treated with pioglitazone vs 1.2% ofplacebo-treated patients. Most of these events were considered mild or moder-ate in intensity (see PRECAUTIONS, General: Pioglitazone hydrochloride).Postmarketing reports of new onset or worsening diabetic macular edema withdecreased visual acuity have also been received (see PRECAUTIONS, General:Pioglitazone hydrochloride).Laboratory AbnormalitiesHematologic: Pioglitazone may cause decreases in hemoglobin and hematocrit.The fall in hemoglobin and hematocrit with pioglitazone appears to be doserelated. Across all clinical studies, mean hemoglobin values declined by 2%-4%in patients treated with pioglitazone.These changes generally occurred within thefirst 4-12 weeks of therapy and remained relatively stable thereafter. Thesechanges may be related to increased plasma volume associated with pioglitazonetherapy and have rarely been associated with any significant hematologic clinicaleffects (see PRECAUTIONS, General: Pioglitazone hydrochloride).

In controlled clinical trials of metformin at 29 weeks duration, a decreaseto subnormal levels of previously normal serum vitamin B12 levels, withoutclinical manifestations, was observed in ~7% of patients. Such decrease,possibly due to interference with B12 absorption from the B12-intrinsic factorcomplex, is, however, very rarely associated with anemia and appears to berapidly reversible with discontinuation of metformin or vitamin B12 supple-mentation (see PRECAUTIONS, General: Metformin hydrochloride).Serum Transaminase Levels: During all clinical studies in the U.S., 14/4780(0.30%) patients treated with pioglitazone had ALT values 3x the ULN duringtreatment. All patients with follow-up values had reversible elevations in ALT. Inthe population of patients treated with pioglitazone, mean values for bilirubin,AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit com-pared with baseline. Fewer than 0.9% of patients treated with pioglitazone werewithdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General:Pioglitazone hydrochloride).CPK Levels: During required laboratory testing in clinical trials with pioglitazone,sporadic, transient elevations in creatine phosphokinase levels (CPK) wereobserved. An isolated elevation to >10x the ULN was noted in 9 patients (valuesof 2150-11400 IU/L). Six of these patients continued to receive pioglitazone,two patients had completed receiving study medication at the time of theelevated value and one patient discontinued study medication due to theelevation. These elevations resolved without any apparent clinical sequelae.The relationship of these events to pioglitazone therapy is unknown.OVERDOSAGEPioglitazone hydrochlorideDuring controlled clinical trials, one case of overdose with pioglitazone wasreported.A male patient took 120 mg per day for four days, then 180 mg per dayfor seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should beinitiated according to patients clinical signs and symptoms.Metformin hydrochlorideOverdose of metformin hydrochloride has occurred, including ingestion ofamounts >50 grams. Hypoglycemia was reported in ~10% of cases, butno causal association with metformin hydrochloride has been established.Lactic acidosis has been reported in ~32% of metformin overdose cases(see WARNINGS, Metformin hydrochloride). Metformin is dialyzable witha clearance of 170 mL/min under good hemodynamic conditions.Therefore, hemodialysis may be useful for removal of accumulated met-formin from patients in whom metformin overdosage is suspected.Rx onlyManufactured by:Takeda Pharmaceutical Company LimitedOsaka, JAPANMarketed by:Takeda Pharmaceuticals America, Inc.One Takeda ParkwayDeerfield, IL 6001505-1134, November 2006GLUCOPHAGE is a registered trademark of Merck Sante S.A.S., anassociate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.ACTOS and ACTOPLUS MET are trademarks of Takeda PharmaceuticalCompany Limited and used under license by Takeda PharmaceuticalsAmerica, Inc.2006, Takeda Pharmaceuticals America, Inc.L-PIOM-00015

Table 2. Adverse Events That Occurred in 5% of Patients in Any Treatment Group During the 24-Week Study

Pioglitazone 30 mg Pioglitazone 45 mg+ metformin + metformin

N=411 N=416n (%) n (%)

Upper Respiratory Tract Infection 51 (12.4) 56 (13.5)Diarrhea 24 (5.8) 20 (4.8)Nausea 24 (5.8) 15 (3.6)Headache 19 (4.6) 22 (5.3)Urinary Tract Infection 24 (5.8) 22 (5.3)Sinusitis 18 (4.4) 21 (5.0)Dizziness 22 (5.4) 20 (4.8)Edema Lower Limb 12 (2.9) 47 (11.3)Weight Increased 12 (2.9) 28 (6.7)

Adverse EventPreferred Term

2007 Takeda Pharmaceuticals North America, Inc. PIOM-00151 1/07 Printed in U.S.A.


1. Haffner SM, Lehto S, Rnnemaa T, et al., Mortality from coronaryheart disease in subjects with type 2 diabetes and in nondiabeticsubjects with and without prior myocardial infarction, N Engl JMed, 1998;339:22934.

2. Mazzone T, Reducing cardiovascular disease in patients withdiabetes mellitus, Curr Opin Cardiol, 2005;20:2459.

3. Mazzone T, Strategies in ongoing clinical trials to reducecardiovascular disease in patients with diabetes mellitus andinsulin resistance, Am J Cardiol, 2004;93(suppl):27C31C.

4. Sowers JR, Treatment of hypertension in patients with diabetes.Arch Intern Med, 2004;164:185057.

5. Blood Pressure Lowering Treatment Trialists, Effects of differentblood pressure-lowering regimens on major cardiovascular eventsin individuals with and without diabetes mellitus: results ofprospectively designed overviews of randomized trials, Arch InternMed, 2005;165:141019.

6. Costa J, Borges M, David C, Vaz Carneiro A, Efficacy of lipidlowering drug treatment for diabetic and non-diabetic patients:meta-analysis of randomised controlled trials, BMJ, 2006;332:111524.

7. Hsueh WA, Law RE, PPAR and atherosclerosis: effects on cellgrowth movement, Arterioscler Thromb Vasc Biol, 2001;21:18915.

8. Blaschke F, Spanheimer R, Khan M, Law R, Vascular effects ofTZDs: new implications, Vascul Pharmacol, 2006;45:318.

9. Haffner SM, Greenberg AS, Weston WM, et al., Effect ofrosiglitazone treatment on nontraditional markers ofcardiovascular disease in patients with type 2 diabetes mellitus,Circulation, 2002;106:67984.

10. Szapary PO, Bloedon LT, Samaha FF, et al., Effects of pioglitazoneon lipoproteins, inflammatory markers, and adipokines innondiabetic patients with metabolic syndrome, Arterioscler ThrombVasc Biol, 2006;26:1828.

11. Miyazaki Y, Mahankali A, Wajcberg E, et al., Effect of pioglitazoneon circulating adipocytokine levels and insulin sensitivity in type 2diabetic patients, J Clin Endocrinol Metab, 2004;89:431219.

12. Goldberg RB, Kendall DM, Deeg MA, et al., A comparison of lipidand glycemic effects of pioglitazone and rosiglitazone in patientswith type 2 diabetes and dyslipidemia, Diabetes Care, 2005;28:154754.

13. Satoh N, Ogawa Y, Usui T, et al., Antiatherogenic effect of

pioglitazone in type 2 diabetic patients irrespective of theresponsiveness to its antidiabetic effect, Diabetes Care,2003;26:24939.

14. Sidhu JS, Cowan D, Kaski JC, The effects of rosiglitazone, aperoxisome proliferator-activated receptor-gamma agonist, onmarkers of endothelial cell activation, C-reactive protein, andfibrinogen levels in nondiabetic coronary artery disease patients,J Am Coll Cardiol, 2003;42:175763.

15. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC, Effect of rosiglitazoneon common carotid intima-media thickness progression incoronary artery disease patients without diabetes mellitus,Arterioscler Thromb Vasc Biol, 2004;24:93034.

16. Li AC, Brown KK, Silvestre MJ, et al., Peroxisome proliferator-activated receptor ligands inhibit development of atherosclerosisin LDL receptor-deficient mice, J Clin Invest, 2000;106:52331.

17. Chen Z, Ishibashi S, Perrey S, et al., Troglitazone inhibitsatherosclerosis in apolipoprotein E-knockout mice: pleiotropiceffects on CD36 expression and HDL, Arterioscler Thromb VascBiol, 2001;21:3727.

18. Crouse JR, Imaging atherosclerosis: state of the art, J Lipid Res,2006;47:167799.

19. Hodis HN, Mack WJ, LeBree L, et al., The role of carotid arterialintima-media thickness in predicting clinical coronary events, AnnIntern Med, 1998;128:2629.

20. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, ARBITER: Arterial Biologyfor the Investigation of the Treatment Effects of ReducingCholesterol: a randomized trial comparing the effects ofatorvastatin and pravastatin on carotid intima medial thickness,Circulation, 2002;106:205560.

21. Koshiyama H, Shimono D, Kuwamura N, et al., Inhibitory effect ofpioglitazone on carotid arterial wall thickness in type 2 diabetes,J Clin Endocrinol Metab, 2001;86:34526.

22. Langenfeld MR, Forst T, Hohberg C, et al., Pioglitazone decreasescarotid intima-media thickness independently of glycemic controlin patients with type 2 diabetes mellitus, Circulation,2005;111:252531.

23. Minamikawa J, Tanaka S, Yamauchi M, et al., Potent inhibitoryeffect of troglitazone on carotid arterial wall thickness in type 2diabetes, J Clin Endocrinol Metab, 1998;83:181820.

24. Hodis HN, Mack WJ, Zheng L, et al., Effect of peroxisomeproliferator-activated receptor gamma agonist treatment on

subclinical atherosclerosis in patients with insulin-requiring type 2diabetes, Diabetes Care, 2006;29:154553.

25. Bots ML, Evans GW, Riley WA, Grobbee DE, Carotid intima-mediathickness measurements in intervention studies: design options,progression rates, and sample size considerations: a point of view,Stroke, 2003;34:298594.

26. Bernard S, Serusclat A, Targe F, et al., Incremental predictive valueof carotid ultrasonography in the assessment of coronary risk in acohort of asymptomatic type 2 diabetic subjects, Diabetes Care,2005;28:115862.

27. Wagenknecht LE, Zaccaro D, Espeland MA, et al., Diabetes andprogression of carotid atherosclerosis: the insulin resistanceatherosclerosis study, Arterioscler Thromb Vasc Biol,2003;23:103541.

28. Kim SH, Lee SJ, Kang ES, et al., Effects of lifestyle modification onmetabolic parameters and carotid intima-media thickness inpatients with type 2 diabetes mellitus, Metabolism, 2006;55:10539.

29. Yokoyama H, Katakami N, Yamasaki Y, Recent advances ofintervention to inhibit progression of carotid intima-mediathickness in patients with type 2 diabetes mellitus, Stroke,2006;37:242027.

30. Dormandy JA, Charbonnel B, Eckland JA, et al., Secondaryprevention of macrovascular events in patients with type 2diabetes in the PROactive study (PROspective pioglitAzone ClinicalTrial In macroVascular Events): a randomised controlled trial,Lancet, 2005;366:127989.

31. Hetzel J, Balletshofer B, Rittig K, Rapid effects of rosiglitazonetreatment on endothelial function and inflammatory biomarkers,Arterioscler Thromb Vasc Biol, 2005;25:18049.

32. Campia U, Matuskey LA, Panza JA, Peroxisome proliferator-activatedreceptor-gamma activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with majorcardiovascular risk factors, Circulation, 2006;113:86775.

33. Zanchetti A, Bond G, Hennig M, et al., Calcium antagonistlacidipine slows down progression of asymptomatic carotidatherosclerosis: principal results of the European Lacidipine Studyon Atherosclerosis (ELSA), a randomized, double-blind, long-termtrial, Circulation, 2002;106:242227.


30 U S C A R D I O V A S C U L A R D I S E A S E 2 0 0 7

as an active comparator, we also cannot definitively rule out that the

treatment difference was due to a proatherogenic effect of glimepiride. We

believe, however, that this explanation is somewhat unlikely in view of the

fact that the treatment difference was largely the result of an effect of

pioglitazone to suppress or delay the progression of CIMT. Our study also

had a dropout rate that approximated 30%. However, dropout rates were

balanced in the two treatment groups, and the participants who remained

in the study (i.e., the CIMT population) were similar to those in the

intention-to-treat population. In addition, an analysis of baseline

characteristics of participants who dropped out showed no difference

compared with those who remained in the study. Finally, thiazolidinediones

may cause acute changes in intravascular volume and affect vascular tone.

Such changes also result from antihypertensive therapy, and an issue has

been discussed in the literature regarding a potential role for changes in

intravascular volume, vascular tone, or both in producing rapid changes in

CIMT.18 In the current study, the observation that treatment difference

appeared to increase over time argues against an important role for

changes in intravascular volume or vascular tone. In a recent evaluation of

the effect of antihypertensive therapy on CIMT, Zanchetti et al.33 concluded

that only 1% of CIMT change could be attributed to overall change in

carotid artery diameter.

Notwithstanding these limitations, our results demonstrate, in a relatively

large and long-term randomized trial, that pioglitazone slowed progression

of CIMT compared with glimepiride. This benefit was measured in

participants with excellent blood pressure control, statin use greater than

50%, and mean LDL-C levels of 113.8mg/dl (SD, 2.4) (2.95 [SD, 0.062]

mmol/l). Additional data will be needed to determine the clinical

significance of these findings: specifically, whether a strategy of routine use

of pioglitazone instead of glimepiride substantially reduces major

cardiovascular events.

Republished with permission from The Journal of the American

Medical Association.

Diabetes, which confers increased risk of

cardiovascular disease, also accelerates

carotid intima-media thickness

progression. However, carotoid intima-

media thickness progression rates vary

widely in patients with diabetes...


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