Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure

Am J Cardiovasc Drugs 2006; 6 (5): 297-304CURRENT OPINION 1175-3277/06/0005-0297/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Thiazolidinediones in Patients with DiabetesMellitus and Heart FailureImplications of Emerging Data

David P. Macfarlane and Miles Fisher

Diabetes Centre, Glasgow Royal Infirmary, Glasgow, UK

Individuals with diabetes mellitus have an increased risk of developing heart failure, usually as a consequenceAbstractof coronary artery disease, although a specific diabetic cardiomyopathy, secondary to a microangiopathy, mayalso exist. The thiazolidinediones, a relatively new class of insulin-sensitizing agents used in the management oftype 2 diabetes mellitus, have a number of complex metabolic actions on surrogate markers of atherogenesis,supported by the results of the recently published PROACTIVE (PROspective pioglitAzone Clinical Trial InmacroVascular Events) trial. Unfortunately, the use of thiazolidinediones in individuals with diabetes mellitusand heart failure is limited because of a propensity to cause fluid retention. The underlying mechanisms of fluidretention have yet to be fully elucidated, but appear to be a dose-related class effect, exacerbated by combinationtherapy with insulin, and in some cases may be localized to peripheral edema. In parallel, echocardiographicstudies show no significant effect of thiazolidinediones on cardiac structure or function.

The design of epidemiologic studies describing an increased risk of developing heart failure in individualswith type 2 diabetes mellitus prescribed thiazolidinediones has been questioned, and a study of ‘new users’ ofantihyperglycemic treatments found no increased risk of hospitalization for heart failure with thiazolidinedionetherapy. There is also increasing evidence for the potential benefits of insulin sensitization in patients withdiabetes mellitus and known heart failure, and a large observational study of over 16 000 patients with a principaldischarge diagnosis of heart failure found a reduced mortality (hazard ratio [HR] 0.87; 95% CI 0.80, 0.94) inthose prescribed thiazolidinediones. This benefit was offset by an increased risk of readmission with heart failure(HR 1.06; 95% CI 1.00, 1.09).

Despite an increase in fluid-related events, recent studies suggest that individuals with type 2 diabetesmellitus and heart failure (New York Heart Association grade I/II) can be treated with thiazolidinediones withappropriate monitoring and adjustment of heart failure therapies. These findings would suggest the need forlarge-scale, prospective trials to investigate the safety and potential benefits of thiazolidinedione use in patientswith diabetes mellitus and heart failure.

Heart failure describes a clinical syndrome of signs and symp- with type 2 diabetes mellitus are at increased risk of developingtoms of pulmonary congestion due to abnormal systolic or diastol- heart failure, usually as a consequence of coronary artery dis-ic heart function, although no unequivocal definition exists.[1] The ease,[4] although a specific diabetic cardiomyopathy, secondary toleading cause of heart failure in the developed world is coronary a microangiopathy, may also exist.[5] Furthermore, in individualsartery disease, which is closely linked to hypertension and diabetes without diabetes mellitus, increased insulin resistance is associat-mellitus.[2] ed with risk of subsequent development of heart failure,[1] and

patients with diabetes mellitus and established heart failure have aType 2 diabetes mellitus is a chronic, progressive conditionpoorer prognosis than patients without diabetes mellitus.[6]characterized by insulin resistance and progressive loss of pancre-

atic β-cell function leading to hyperglycemia and the development The thiazolidinediones (glitazones) are a relatively new class ofof microvascular and macrovascular complications.[3] Individuals insulin-sensitizing drug licensed for the management of type 2

298 Macfarlane & Fisher

diabetes mellitus,[7] targeting insulin resistance, one of the key 1.1 Diabetic Cardiomyopathy

factors underlying the pathogenesis of type 2 diabetes mellitus.[8]

A specific ‘diabetic cardiomyopathy’ relating to a microangi-The thiazolidinediones have a number of complex metabolic ac-opathy not detectable on coronary angiography has been proposed

tions on parameters of cardiovascular risk, but despite the potentialto exist, thereby contributing to the incidence of heart failure in

benefits of these agents, concerns over cardiotoxicity and theirdiabetes mellitus.[5] It has been demonstrated that regional abnor-

propensity to cause fluid retention potentially limit their use inmalities in myocardial function can be secondary to autonomic

patients with diabetes mellitus and heart failure.[9] In this articledysfunction in patients with diabetes mellitus.[15] A number of

we discuss potential adverse effects of thiazolidinediones and additional factors may contribute to this increased risk of develop-review the evidence supporting the use of thiazolidinediones in ing ventricular dysfunction in individuals with diabetes mellitusindividuals with diabetes mellitus and heart failure. including: reduced oxidative glucose metabolism, increased fatty

acid metabolism,[16] and alterations in intracellular calcium home-ostasis and gene expression which relate to cardiac energy metab-1. Diabetes Mellitus and Heart Failureolism.[17,18]

The increased cardiovascular morbidity and mortality associat-2. The Thiazolidinedionesed with type 2 diabetes mellitus was clearly established in the

Framingham study.[10] Data from the Framingham cohort alsodemonstrated that heart failure was 2.4-fold more common in men 2.1 Pharmacologywith diabetes mellitus (p < 0.05), and 5.1-fold more common in

The thiazolidinediones are agonists of peroxisome proliferatorwomen with diabetes mellitus (p < 0.01), than in sex-matchedactivated receptor (PPAR)-γ, a nuclear receptor strongly expressedcontrols 45–74 year of age.[4] These findings were independent ofin adipose tissue. Their action produces an increase in transcrip-hypertension and ischemic heart disease. A more recent study[6]

tion of various insulin-sensitive genes including SLC2A4 (encod-examining the electronic medical records of almost 8500 patientsing glucose transporter subtype 4 [GLUT4]) and SLC27A1 (encod-

with type 2 diabetes mellitus found the prevalence of heart failureing fatty acid transport subtype 1 [FATP1]), with their maximal

to be 11.8%, compared with 4.5% in age- and sex-matched con-action taking up to 3 months to develop.[7] Thiazolidinediones lead

trols. Furthermore, with the increasing incidence of diabetes mel-to a sustained improvement in glycemic control through improved

litus, an aging population, and more patients surviving myocardialinsulin sensitivity and pancreatic β-cell function.[19] Pioglitazone

infarction, the incidence of heart failure is expected to increase.and rosiglitazone are the two thiazolidinediones currently availa-

The true prevalence of cardiac dysfunction in individuals with ble and appear to have a safer adverse effect profile than trog-diabetes mellitus is difficult to determine because of the differ- litazone which was withdrawn in 1997 because of concerns overences in criteria and methods used in diagnosis. It is therefore hepatotoxicity.[20,21] They are currently licensed for use as combi-likely that the results from the Framingham study are an underesti- nation or monotherapy, or with insulin (although this is not cur-mate as the investigators used the clinical diagnosis of heart failure rently licensed in Europe).as opposed to echocardiographic findings.[11] It is also noteworthy

2.2 Beneficial Cardiovascular Propertiesthat up to 60% of patients with type 2 diabetes mellitus have beenshown to have diastolic dysfunction when using sensitive echo-

There is surmounting evidence that insulin-sensitizing agentscardiographic screening methods.[12]

such as metformin and the thiazolidinediones have importantA number of factors contribute to the risk of developing heart antiatherosclerotic properties, additional to their antihyperg-

failure in diabetes mellitus; for example, poor glycemic control lycemic effects. Thiazolidinediones have been shown to promoteleads to an 8% increase in relative risk for every 1% increase in beneficial changes on surrogate markers of cardiovascular risk,glycosylated hemoglobin (HbA1c).[13] Other factors that have been with improvements in lipid profiles,[22] BP,[23,24] endothelial dys-shown to independently increase the risk of developing heart function,[25] inflammatory indices,[26] progression of atherosclero-failure in diabetes mellitus include age, duration of diabetes mel- sis (as measured by carotid intima media thickness),[27] and re-litus, insulin use, elevated serum creatinine and the presence of duced rates of restenosis in patients with type 2 diabetes mellitusischemic heart disease.[11] Once developed, individuals with diabe- following coronary artery stent insertion.[28]

tes mellitus and heart failure also appear to have a poorer progno- There is also increasing interest in the role of thiazolidinedionessis than patients without diabetes mellitus.[14] and the renin-angiotensin system. Heart failure is associated with

© 2006 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2006; 6 (5)

Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure 299

neurohormonal activation and increased activity of the sympathet- ography.[45] However, retrospective studies are limited by theiric nervous system and renin-angiotensin system. Inhibition of the design and the natural inclusion of high-risk patients requiring therenin-angiotensin system improves ventricular remodeling and introduction of thiazolidinediones, compared with those stable onsurvival in patients with heart failure.[29] The thiazolidinediones current therapy.[46] To avoid confounding, one prospective, non-may also have beneficial effects on the renin-angiotensin system, randomized trial therefore examined >23 000 patients with type 2such as reduced angiotensin type 1 receptor expression, although diabetes mellitus who recently received new antidiabetic agentsthe clinical significance of these are unclear.[30,31] There is also (‘new users’). This trial found no significant increase in hospital-evidence of decreased production of tumor necrosis factor-α,[32] izations for heart failure in the pioglitazone group versus theimplicated in the progression of heart failure, following thiazo- sulphonylurea group (hazard ratio [HR] 1.28; 95% CI 0.85, 1.92)lidinedione treatment. Furthermore, endothelin 1 levels, which are after adjusting for various demographics, although mean follow-normally increased and of prognostic value in heart failure, are up was only 10.2 months.[46] An increase in admissions for heartfound to be decreased following thiazolidinedione treatment.[33,34] failure was found in the insulin-treated group (HR 1.56; 95% CI

1.00, 2.45). Interestingly, a decrease in hospital admissions withheart failure was found in the metformin group, supporting the2.3 Adverse Effectsbenefit of insulin sensitization and highlighting that the resultswith thiazolidinediones are highly dependent on the comparativeCommon adverse effects of the thiazolidinediones includetreatment group (the sulphonylureas).weight gain, partly through increased adipogenesis,[35] and also

fluid retention.[7] The latter of these can produce a dilutional2.4 Mechanisms of Fluid Retention and Peripheral Edemaanemia,[36] peripheral edema, and perhaps more seriously can lead

to exacerbations, or unmasking of previously undiagnosed heart The mechanisms behind thiazolidinedione-induced fluid reten-failure, especially when combined with insulin.[9] Fluid retention tion have yet to be fully elucidated, although it is clear thatis a class effect of the thiazolidinediones and occurs in a dose- peripheral edema can develop without co-existing cardiac dys-dependent manner, with no significant difference existing between function.[47] This may in part relate to calcium channel blockingthe different thiazolidinediones.[37,38] The manufacturers report the properties producing edema in a similar manner to the dihydropy-incidence of peripheral edema as 2–5% for monotherapy, increas- ridine subgroup of calcium channel antagonists.[48] Theing to 5–15% for combination treatment with insulin.[39-41] Simi- thiazolidinediones can also increase circulating levels of certainlarly weight gain appears to be greater with combination therapy, growth factors, for example, vascular endothelial growth factor,and is similar for both thiazolidinediones.[37,38]

which increases vascular permeability.[49] These explanations,A retrospective case-control (chart review) study of 111 pa- suggesting vascular ‘leakiness’, would be supported by reports of

tients with diabetes mellitus and chronic systolic heart failure edema resistant to diuretic therapy which is easily reversible ontreated with thiazolidinediones, including 63% of patients on discontinuation of therapy.[42]

combination therapy with insulin, found the incidence of peripher- Clearly, localized ankle edema does not lead to true exacerba-al edema to be 17.1%.[42] However, other investigators have actu- tions of heart failure (although it may be classed as such inally suggested this to be an underestimation as a result of limita- controlled trials; section 2.6). Studies with troglitazone demon-tions of the study design.[43] The investigators concluded that the strated effects on the renal microcirculation which could lead toedema was generally peripheral, usually reversible after stopping reduced glomerular filtration pressure and increased fluid reten-the thiazolidinedione and was independent of the severity of tion via mechanisms involving voltage-gated calcium channels,[50]

cardiac dysfunction as assessed by echocardiography and New and a further mechanism may involve PPAR-γ effects on the renalYork Heart Association (NYHA) class at baseline,[42] suggesting it collecting duct.[51,52] Lastly, the thiazolidinediones may simplyis difficult to predict clinically which patients will develop signs of potentiate the renal effects of insulin on sodium and water reten-peripheral edema or fluid retention. It is also difficult to predict the tion,[53] which may be relevant when considering combinationonset of fluid retention, which although generally occurs between therapy with thiazolidinediones and insulin.8–12 weeks, can occur rapidly, or take up to 13 months to develop,suggesting that there may be additional mechanisms to those 2.5 Effects on Cardiac Functioninvolving PPAR-γ.[11,44]

A further retrospective review of six obese patients developing Original animal studies found evidence of changes in cardiacclinical heart failure receiving thiazolidinedione treatment found structure with increased left ventricular mass developing follow-all six to have evidence of diastolic dysfunction on echocardi- ing troglitazone therapy.[54] In contrast, other animal studies have



demonstrated improved ventricular remodeling following 2.6 Cardiovascular Outcome Studies

glitazone therapy after experimental myocardial ischemia.[55]

The recently published PROACTIVE (PROspective piog-Work previously undertaken with troglitazone investigated thelitAzone Clinical Trial In macroVascular Events) study was aeffect of thiazolidinediones on cardiac structure and function inlarge European placebo-controlled, multicenter trial of >5000humans; 154 patients with type 2 diabetes mellitus, with a meanhigh-risk patients with type 2 diabetes mellitus and establishedduration of 6 years, were randomized to either troglitazone orcardiovascular disease.[59] This secondary prevention study wasglibenclamide (glyburide) with dose titration, for a 48-week studydesigned to assess the effect of ‘add on’ therapy with pioglitazoneevaluating changes in left ventricular mass index (LVMI), cardiacon macrovascular mortality and morbidity. Patients with NYHAindex (CI), and stroke volume index (SVI) assessed by two dimen-class II–IV heart failure were excluded. A 10% reduction in thesional echocardiography and pulsed-wave Doppler. Blinded as-primary composite endpoint was observed, although this failed tosessment at 24 and 48 weeks found no statistically significantreach statistical significance (p = 0.095). However, a significantdifference in LVMI between the treatment groups. Interestingly,reduction in the prespecified secondary composite endpoint of all-significant increases in CI and SVI were found in the troglitazonecause mortality, nonfatal myocardial infarction and stroke wasgroup, associated with a reduction in estimated peripheral resis-observed (HR 0.84; 95% CI 0.72, 0.98; p = 0.027) [figure 1].tance and diastolic pressures. Ten percent of patients reportedThere was a significant increase in cases of reported heart failureperipheral edema, but there were no reports of suspected heartin the pioglitazone group compared with placebo (11% vs 8%;failure.[56]

p = 0.0001). However, these results should be interpreted withA similar 52-week study of 203 patients with type 2 diabetes caution given the probable inclusion of individuals with isolated

mellitus was performed using rosiglitazone (or glibenclamide) and peripheral edema and that the results were not centrally adjudicat-found no significant effect on cardiac structure or function. No ed. Perhaps in keeping with this, there was no increase in deathsincrease in ejection fraction was noted in the rosiglitazone group. attributed to heart failure between the two treatment groups.[60] APatients were excluded if there was a previous history of myocar- further positive outcome from the trial was a reduction in the needdial infarction, class III–IV NYHA heart failure, or marked evi- to commence insulin therapy in the pioglitazone group, which maydence of left ventricular hypertrophy at baseline.[57] An increased have implications for the development of symptoms or signs ofincidence of peripheral edema occurred in the rosiglitazone group, heart failure.although this did not lead to any cases of withdrawal from the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes andstudy. Small increases in left ventricular end-diastolic volume Regulation of Glycaemia in Diabetes) is a long-term (6-year)(LVEDV), consistent with increased plasma volume, were found randomized, open-label study in >4000 patients with inadequatelyat the end of the 1-year study in both treatment groups. In the controlled type 2 diabetes mellitus receiving metformin orrosiglitazone treatment group this effect on LVEDV was more sulphonylurea alone.[61] The aim of this study is to assess noninfer-marked in those with a body mass index >27 kg/m2, suggestingthat plasma volume expansion may be more likely in obese indi-viduals.

In this trial[57] of rosiglitazone versus glibenclamide the studypopulation was not representative of patients with type 2 diabetesmellitus, as individuals receiving antihypertensive medicationswere excluded because of their possible confounding effects. Morerecent data published in abstract form, specifically investigatingpatients with type 2 diabetes mellitus and NYHA class I–II heartfailure receiving appropriate therapy, again found no effect oncardiac function or structure after 1 year of treatment with rosig-litazone (4–8 mg/day) versus placebo.[58] Heart failure treatmentswere adjusted as necessary, with an increase in diuretic require-ments in the rosiglitazone group. More fluid-related events includ-ing peripheral edema and dyspnea were noted in the rosiglitazonegroup, more so in the NYHA II group, but generally were notsufficient to lead to treatment withdrawal or hospitalization.[58]

0

5

10

15

20

25

0 6 12 18 24 30 36

Numbers at riskPioglitazonePlacebo

25362566

24872504

24352442

23812371

23362315

396390

Time from randomization (months)

Pro

port

ion

of e

vent

s (%

)

Pioglitazone (301 events)Placebo (358 events)

Fig. 1. Results of the PROACTIVE (PROspective pioglitAzone Clinical TrialIn macroVascular Events) study (reproduced from Dormandy et al.,[59] withpermission). Kaplan-Meier curve of time to main secondary endpoint(death, myocardial infarction, and stroke).



iority of the rosiglitazone group with a primary endpoint of time to associated with an increased readmission rate as a result of heartfirst cardiovascular hospitalization or death. Although perhaps not failure (HR 1.17; 95% CI 1.05, 1.30).[65]

examining such a high-risk group of patients as the PROACTIVE As the investigators point out, these observational studies arestudy, the RECORD study will hopefully provided further infor- limited by their design and an inability to control for all possiblemation on the safety and tolerability of thiazolidinediones in confounders including changes to patients’ prescriptions follow-clinical practice. ing hospital discharge, exacerbations of heart failure not requiring

readmission to hospital, confounding by indication altering choiceof medication, and severity of diabetes mellitus or heart failure.2.7 Thiazolidinedione Use in Patients with Heart FailureAdditionally, variations in coding of diagnosis or lack of adjust-ment for other interim interventions are other potential confound-Despite current recommendations and concerns over the use ofers. However, these studies do provide support for the potentialthiazolidinediones in patients with heart failure, there is evidencebenefits of insulin-sensitizer therapy with thiazolidinediones inthat this guidance is not being strictly adhered to. A large retro-selected patients with diabetes mellitus, heart failure and knownspective observational study demonstrated that up to 16% ofischemic heart disease.patients with diabetes mellitus >65 years of age, with a principal

discharge diagnosis of heart failure, were prescribed a thiazo-lidinedione on discharge, although the investigators were unable 3. Conclusionsto assess NYHA classification.[62] In addition, 11% of patientswere discharged receiving metformin, which is similarly contrain- The PPAR-γ agonists or thiazolidinediones are a relatively newdicated in patients with heart failure because of concerns over an class of oral antidiabetic agents targeting insulin resistance, theincreased risk of developing lactic acidosis.[63] main pathogenetic factor in type 2 diabetes mellitus. The

thiazolidinediones now have proven efficacy in reducing cardio-These findings confirm that insulin-sensitizing agents are usedvascular risk[59] and may also have additional beneficial effects onin large numbers of patients with heart failure. Using a cohortthe renin-angiotensin system.[31] However, there are still concernsderived from the National Heart Care Project, the investigatorsover their use in individuals with diabetes mellitus and heartwent on to examine the possible adverse effects of the prescriptionfailure because of their propensity to cause fluid retention. As aof insulin-sensitizing agents in elderly individuals with knownresult of this, the American Heart Association and Americanheart failure via a retrospective study of 16 417 Medicare benefi-Diabetes Association recently published a consensus statement onciaries with a principal discharge diagnosis of heart failure. 2226the use of thiazolidinediones inpatients with heart failure, althoughpatients were prescribed a thiazolidinedione, 1861 metformin anddisagreement exists.[9,66]261 both agents. Adjusting for multiple variables using a mul-

tivariable hierarchical Cox proportional hazards models, the inves- Patients with type 2 diabetes mellitus are a high-risk group withtigators found that treatment with a thiazolidinedione was associ- an increased risk of developing heart failure, usually as a conse-ated with a reduced mortality (HR 0.87; 95% CI 0.80, 0.94). A quence of ischemic heart disease.[4] Epidemiologic studies andsimilar benefit was seen with metformin therapy (HR 0.87, 95% case series describe an increased risk of developing new-onsetCI 0.78, 0.97), which was also associated with a lower risk of heart failure in individuals with type 2 diabetes mellitus treatedreadmission with heart failure (HR 0.92; 95% CI 0.92, 0.99). with thiazolidinediones.[45,67,68] It has been suggested that theseHowever, an increase in risk of readmission with heart failure was findings can be explained by flaws in the design of the epidemio-seen in the thiazolidinedione group (HR 1.06; 95% CI 1.00, logic studies.[46,69] These results may deter physicians from pre-1.09).[64] There appeared to be no significant difference in sub- scribing thiazolidinediones in individuals with known heart failuregroups comparing differing severities of left ventricular ejection or other high-risk patients. However, these patients may have thefractions and in those with or without coronary artery disease. most to benefit from insulin sensitization, supported by increasing

evidence from large, observational studies demonstrating reducedA further retrospective cohort study performed by the samemortality in individuals with diabetes mellitus and heart failureinvestigators of almost 9000 Medicare patients with diabetesprescribed thiazolidinediones (table I).[64,65]mellitus discharged following acute myocardial infarction and

receiving oral antidiabetic agents, found no increase in mortality Currently, in the US, the thiazolidinediones are contraindicatedwith metformin or thiazolidinedione prescription and in fact found in NYHA class III and IV heart failure as these individuals werea reduction in 1-year mortality in those prescribed both agents (HR excluded from clinical trials initially evaluating thiazolidinedione0.52; 95% CI 0.34, 0.82). The results were similar in patients with safety and efficacy. In the UK the thiazolidinediones are contrain-known heart failure. Thiazolidinedione prescription was again dicated in all patients with a history of heart failure and are not



Table I. Studies of thiazolidinedione (TZD) use in patients with and without known heart failure (HF) and type 2 diabetes mellitus

Study Study design Diabetic patient group HF patients Findingsincluded

Karter et al.[46] Retrospective cohort 23 440 ‘new users’ of oral No No significant increase in hospitalizationantidiabetic drugs in community- for HF with TZD (pioglitazone) [HR 1.28;based cohort 95% CI 0.85, 1.92]. Mean follow-up 10.2

months

Dargie et al.[58] Prospective 224 HF patients randomized to NYHA class I and II No adverse effect of rosiglitazone onrosiglitazone or placebo only cardiac structure or function at 1 year, but

more fluid-related events in the TZD group

Dormandy et al.[59] Prospective, 5238 with known macrovascular NYHA class I only Reduced all-cause mortality, nonfatal MI,randomized, controlled disease randomized to pioglitazone and stroke (HR 0.84; 95% CI 0.72, 0.98),trial or placebo but increased risk of nonadjudicated HF

Masoudi et al.[64] Retrospective cohort 16 417 patients discharged with Yes Reduced 1-year mortality with TZD usediagnosis of HF (HR 0.87; 95% CI 0.8, 0.94), but increased

risk of readmission with HF

Inzucchi et al.[65] Retrospective cohort 8872 patients discharged on oral Yes Reduced 1-year mortality in thoseantidiabetic drugs following MI prescribed both metformin and TZD (HR

0.52; 95% CI 0.34, 0.82), but increasedrisk of readmission with HF with TZD use

HR = hazard ratio; MI = myocardial infarction; NYHA = New York Heart Association.

licensed for use with insulin,[70] although this may change follow- The evidence suggests that despite increases in fluid-relateding the results of the recent PROACTIVE study. It is difficult to events, thiazolidinediones do not have any adverse effects onpredict which patients with heart failure will develop clinical cardiac structure or function, implying that reported cases of newsymptoms and signs of fluid overload with thiazolidinedione heart failure are most likely unmasking of heart failure in thistreatment when assessed by both NYHA status and left ventricular high-risk population. No changes in cardiac structure or functionejection fraction at baseline,[42] and there appears to be no signifi- are seen in patients with NYHA class I–II heart failure on appro-cant difference between thiazolidinediones and the incidence of priate heart failure therapy.[58] Furthermore, despite associatedperipheral edema.[37,38] Preliminary studies have investigated the increases in peripheral edema and dyspnea, it seems this can oftenpredictive role of elevated B-type natriuretic peptide levels at be managed with appropriate adjustment of heart failure treat-baseline.[71,72] ment.[58] It therefore seems prudent that patients with heart failure

and diabetes mellitus should be monitored closely if the introduc-It should be noted that the alternative to the addition oftion of a thiazolidinedione is to be considered and need to bethiazolidinedione therapy is often insulin, which has known ef-informed regarding when to contact their physician to ensurefects on fluid retention, and is also associated with an increasedtimely treatment adjustment. Similarly, given the high cardiovas-risk of admissions with heart failure.[46,73] Similarly, the insulincular risk of individuals with type 2 diabetes mellitus, physicianssecretagogues, including the sulphonylureas, act to increase insu-need to be alert to the possibility of exacerbating previouslylin secretion potentially increasing the risk of insulin-related fluidundiagnosed heart failure.retention. There are also longstanding concerns that the sulphony-

lureas may adversely affect cardiovascular risk,[74] possibly There is increasing evidence supporting insulin sensitizationthrough their action on cardiac potassium adenosine triphos- with thiazolidinediones in individuals with type 2 diabetes mel-phatase channels, rendering the myocardium susceptible to ische- litus and heart failure. These benefits are offset by increases inmic injury by preventing ischemic preconditioning.[75] However, fluid-related events and increased hospital admissions for heartno adverse cardiac effects of sulphonylyureas were demonstrated failure. However, some studies suggest this can be managed byin the UKPDS (UK Prospective Diabetes Study) group.[76] Finally, close monitoring of fluid balance and adjustment of diuretics asthe other insulin-sensitizing agent, metformin, which does not necessary. These findings suggest we need large-scale, prospec-cause fluid retention, is also contraindicated in patients with heart tive trials to investigate the safety and potential benefits of thiazo-failure, because of concerns over lactic acidosis, and its use is lidinedione use in patients with type 2 diabetes mellitus and heartrestricted in patients with renal dysfunction.[63] failure.



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Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure

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