Thiazolidinediones, Metformin, and Outcomes in Older Patients With Diabetes and Heart Failure
An Observational Study
Background— Insulin-sensitizing drugs of the thiazolidinedione class and metformin are commonly prescribed to treat diabetes in patients with heart failure despite strong warnings from the Food and Drug Administration against this practice. Whether this results in adverse outcomes is unknown.
Methods and Results— We conducted a retrospective cohort study of 16 417 Medicare beneficiaries with diabetes discharged after hospitalization with the principal discharge diagnosis of heart failure. The association between antidiabetic drug prescriptions and outcomes was assessed in multivariable hierarchical Cox proportional hazards models, with adjustment for patient, physician, and hospital variables and accounting for the clustering of patients within hospitals. The primary outcome of the study was time to death due to all causes. Secondary outcomes included time to readmission for all causes or for heart failure. Crude 1-year mortality rates were lower among the 2226 patients treated with a thiazolidinedione (30.1%) or the 1861 treated with metformin (24.7%) compared with that among the 12 069 treated with neither insulin-sensitizing drug (36.0%, P=<0.0001 for both comparisons). In multivariable models, treatment with the thiazolidinediones (hazard ratio [HR] 0.87, 95% CI 0.80 to 0.94) or metformin (HR=0.87, 95% CI 0.78 to 0.97) was associated with significantly lower risks of death. There was no association with treatment with sulfonylureas (HR=0.99, 95% CI 0.91 to 1.08) or insulin (HR=0.96, 95% CI 0.88 to 1.05) and mortality. Admissions for all causes did not differ with either insulin sensitizer. There was a higher risk of readmission for heart failure with thiazolidinedione treatment (HR 1.06, 95% CI 1.00 to 1.09) and a lower risk with metformin treatment (HR 0.92, 95% CI 0.92 to 0.99).
Conclusions— This observational study suggests that thiazolidinediones and metformin are not associated with increased mortality and may improve outcomes in older patients with diabetes and heart failure. Randomized trials are warranted to corroborate these findings.
Received June 15, 2004; revision received October 11, 2004; accepted October 26, 2004.
Heart failure and diabetes are increasingly common and create management challenges when they coexist. Of the available antihyperglycemic agents, not all are considered appropriate for patients with heart failure. Because of concerns of fluid retention with thiazolidinediones and lactic acidosis with metformin, package inserts warn against the use of these drugs in most patients with heart failure.1–3 The US Food and Drug Administration (FDA) has issued precautions for the use of thiazolidinediones in patients with advanced heart failure symptoms4 and has required a “black box” warning against prescribing metformin to patients with heart failure that requires pharmacological treatment.3 Professional organizations have also advised against the use of these drugs in many patients with heart failure.5,6 Despite these warnings, insulin sensitizers are increasingly prescribed to patients with diabetes and heart failure,7 perhaps because of their favorable effects on cardiovascular risk factors or beliefs that the evidence supporting existing precautions is inadequate. Whether this practice is associated with a net benefit or harm is not known.
Accordingly, we assessed the relationship between the prescription of insulin-sensitizing agents and the outcomes of death and rehospitalization among elderly diabetic patients after hospitalization for heart failure in a cohort derived from the National Heart Care Project (NHC). This Medicare population is ideal for this investigation because of the high prevalence and risk of heart failure and diabetes. This study is intended to provide information about the balance of risks and benefits relevant to recommendations for use of these agents.
The NHC is a Centers for Medicare & Medicaid Services (CMS) initiative designed to assess and improve the quality of care for Medicare beneficiaries hospitalized with heart failure. The project data consist of 2 national samples of fee-for-service Medicare beneficiaries hospitalized with a principal discharge diagnosis of heart failure (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 402.01, 402.11, 402.91, 404.01, 404.91, or 428).
The samples included hospitalizations with discharge dates from April 1998 to March 1999 or July 2000 to June 2001, as described previously.7 In each state, up to 800 discharges during both of the 2 sampling frames were randomly selected; in states with fewer than 800 eligible records, all were selected. The hospital records were reviewed for clinical data in central abstraction centers. Data quality was ensured through the use of trained abstractors, the use of abstraction software, and random record reabstraction.
Patients without valid social security numbers, those receiving long-term hemodialysis, those transferred to another hospital, and those who left against medical advice were excluded. The NHC cohort thus consisted of 39 477 records in 1998 to 1999 and 39 405 in 2000 to 2001.
Patients from either sample with diabetes (n=33 532) were identified by documentation in the hospital record or the prescription of an antihyperglycemic medication at hospital admission or discharge. Of these patients, those who died in the hospital, those who were <65 years of age, those who had missing data on vital status or readmission, and those who were discharged to hospice were excluded. Patients not receiving pharmacological treatment for diabetes at discharge were also excluded. These criteria resulted in a sample of 16 417 records, 8672 from 1998 to 1999 and 7745 from 2000 to 2001.
Other Data Sources
Physician characteristics were ascertained from the American Medical Association Physician Masterfile.8 Hospital characteristics were identified with American Hospital Association Annual Surveys.9 Dates of death and readmission were assessed with the Medicare Enrollment Database and Medicare Part A data, respectively.
Independent variables included demographic characteristics, medical history, clinical condition on presentation, laboratory evaluations, medications at discharge, characteristics of the treating attending physician, and hospital. Covariates that reflected diabetes severity included the admission blood glucose level and diabetes complications ascertained with ICD-9 codes in discharge abstracts for the index hospitalization or in any Part A record during the prior year. Candidate complications included nephropathy (ICD-9 code 250.4), retinopathy (250.5), neuropathy (250.6), peripheral circulatory disorders (250.7), and other diabetic complications (250.1, 250.2, 250.3, 250.8, or 250.9). The prescription at discharge of other antihyperglycemic agents (eg, sulfonylureas and insulin) and agents used to treat heart failure and associated conditions, including ACE inhibitors, β-adrenergic receptor blockers, and statins, was also considered.
The primary outcome was time from hospital discharge to death due to any cause. Secondary outcomes included time to first readmission for any cause or for heart failure. Proportions of patients who died or were readmitted at least once in the year after discharge were assessed. Because of the association between metformin and lactic acidosis, rates of readmission for the primary diagnosis of metabolic acidosis (ICD-9 code 276.2, which includes lactic and other forms of metabolic acidosis) were also ascertained.
Differences in patient characteristics according to the prescription of thiazolidinediones or metformin at hospital discharge were assessed with χ2 tests for categorical variables and F tests for continuous variables. Crude event rates were compared with χ2 tests, and unadjusted hazard ratios (HRs) were calculated with univariate Cox statistics. Multivariable Cox models were constructed to assess the independent relationship between thiazolidinedione or metformin prescription and the outcomes, with adjustment for the clustering of patients within hospitals. These models accounted for the possible confounding effects of patient, physician, and hospital characteristics. Beginning with a model that included all variables, those not significantly associated with the outcome (P>0.05) were removed sequentially. Excluded variables were subsequently tested individually for residual confounding and were retained if the HR associated with treatment with metformin or thiazolidinediones changed by >10% with their inclusion. In the readmission models, patients who died before readmission were censored. This was rarely necessary, however, because virtually all such patients (92.2%) experienced a readmission before death.
Subgroup analyses were conducted in prespecified strata of clinical interest. Because the thiazolidinediones available in the United States differed between time periods (troglitazone [Rezulin, Parke-Davis] in 1998 to 1999 and rosiglitazone [Avandia, GlaxoSmithKline] or pioglitazone [Actos, Takeda Pharmaceuticals North America] in 2000 to 2001), stratification by sampling period was performed. Stratification by the presence or absence of coronary artery disease, left ventricular systolic dysfunction, pulmonary edema on chest radiograph, and peripheral edema on presentation was also conducted. Because the risk of fluid retention with thiazolidinediones is reportedly higher in patients also treated with insulin,1,2 and because metformin is not recommended for patients with creatinine levels >132 μmol/L (1.5 mg/dL),3 stratification by these variables was assessed. Statistical analyses were conducted with Stata 7.0 (Stata Corporation) and SAS 8.02 (SAS, Inc).
Among the study population, 12 069 patients did not receive a prescription for an insulin sensitizer, 2226 received a prescription for a thiazolidinedione, 1861 received a prescription for metformin, and 261 patients were discharged with prescriptions for both insulin sensitizers. Patients receiving prescriptions for either a thiazolidinedione or metformin at discharge were on average younger and were more often white than those who did not (Table 1⇓). Patients treated with thiazolidinediones had a prevalence of complications of diabetes comparable to those not treated with an insulin sensitizer except for neurological complications. Patients treated with metformin generally had lower prevalence of diabetes complications than those not treated with an insulin sensitizer. Patients treated with thiazolidinediones at discharge had a higher prevalence of peripheral edema on admission. The majority of patients discharged with an insulin sensitizer were receiving the medication at the time of admission.
Unadjusted 1-year mortality was lower in patients treated with thiazolidinediones (30.1%) or metformin (24.7%) than in those not treated with an insulin sensitizer (36.0%, P<0.0001 for comparison with both groups). After adjustment for patient, provider, and hospital characteristics, sampling time frame, and differences in other medical treatment at discharge, both thiazolidinediones (HR=0.87, 95% CI 0.80 to 0.94; Figure 1) and metformin (HR=0.86, 95% CI 0.78 to 0.97; Figure 2) remained associated with significantly lower risks of death from all causes.
In contrast, there was no significant independent association between the prescription of other antihyperglycemic agents and mortality, including sulfonylureas (HR=0.99, 95% CI 0.91 to 1.08) and insulin (HR=0.96, 95% CI 0.88 to 1.05). Compared with patients not treated with an insulin sensitizer, patients treated with both metformin and a thiazolidinedione also had a lower risk of death (HR=0.76, 95% CI=0.58 to 0.99).
Compared with patients not discharged with a prescription for an insulin-sensitizing agent, those discharged with a prescription for a thiazolidinedione had higher unadjusted rates of readmission both for all causes (72.1% for those not treated versus 74.6%, P=0.02) and for heart failure (64.8% versus 67.6%, P=0.02). In contrast, patients treated with metformin had lower unadjusted rates of readmission for all causes (68.0%, P=0.0003 compared with patients not treated) and for heart failure (58.6%, P<0.0001). In multivariable models, however, there were no differences in the risk for all-cause readmission among patients discharged with a prescription for a thiazolidinedione (HR=1.04, 95% CI 0.99 to 1.10; Table 2) or metformin (HR=0.94, 95% CI 0.89 to 1.01; Table 3) compared with those not treated with an insulin sensitizer (referent). However, there was a modestly higher risk of borderline statistical significance for readmission for heart failure among patients receiving a thiazolidinedione (HR=1.06, 95% CI 1.00 to 1.12) and a lower risk for heart failure readmission with metformin (HR=0.92, 95% CI 0.86 to 0.99).
Patients treated with both a thiazolidinedione and metformin had a significantly lower risk for readmission for all causes (HR=0.82, 95% CI 0.69 to 0.96) and a borderline significantly lower risk for heart failure (HR=0.85, 95% CI 0.71 to 1.01). Readmissions for metabolic acidosis were similar among patients not treated with an insulin sensitizer (2.6%) compared with those discharged with a prescription for metformin (2.3%, P=0.40) or a thiazolidinedione (2.2%, P=0.24).
Both thiazolidinedione prescription and metformin prescription were associated with similar relative reductions in the risk of mortality or readmission among patients with or without coronary artery disease, left ventricular systolic dysfunction, pulmonary edema on chest radiograph, or peripheral edema on presentation (Tables 2 and 3⇑). There was a similar association with a lower risk for mortality with thiazolidinedione prescription in the 1998 to 1999 sample, when troglitazone was prescribed, and the 2000 to 2001 sample, when rosiglitazone and pioglitazone were prescribed (P=0.3 for interaction).
The risk for readmission for all causes or for heart failure among patients treated with a thiazolidinedione compared with patients not treated with an insulin sensitizer did not differ among the strata assessed. The relative risk of readmission for heart failure was similar among thiazolidinedione-treated patients discharged with insulin and those not treated with insulin (P for interaction=0.1; Table 2). The risk of readmission for all causes or for heart failure among patients treated with metformin did not differ between patients with a serum creatinine level <133 μmol/L and those with a higher serum creatinine level (Table 3).
In this observational study, the prescription of thiazolidinediones or metformin was independently associated with a lower risk of death due to all causes in a broad range of older patients with diabetes hospitalized with heart failure. In contrast, there was no association between other forms of diabetes treatment, including the sulfonylureas and insulin, and mortality. The relationship between the prescription of an insulin-sensitizing drug and mortality was similar regardless of the presence of clinically manifest coronary artery disease, left ventricular systolic dysfunction, or elevated serum creatinine. Patients treated with metformin had a lower risk of readmission for heart failure than those not treated with an insulin sensitizer, in contrast to those treated with thiazolidinediones, who had a higher risk for this outcome. However, among patients treated with either insulin sensitizer, there was no increase in the risk of admission for all causes. These findings do not support the existing recommendations against the use of insulin sensitizers in many, if not all, patients with heart failure but emphasize the importance of close monitoring of patients treated with thiazolidinediones.
The treatment of diabetes in patients with heart failure is controversial. Currently, package inserts include a “black box” warning that metformin is contraindicated in patients with “heart failure requiring pharmacological therapy” because such patients may have higher risks for lactic acidosis.3 The thiazolidinediones are not recommended for patients with “New York Heart Association Class III or IV status” because of concerns of provoking worsening heart failure with fluid retention, and because trials of thiazolidinediones have not enrolled such patients.1,2,4 Recently, the American Diabetes Association and the American Heart Association issued a consensus statement advising against the use of thiazolidinediones in patients with advanced heart failure symptoms.5 Nevertheless, clinicians commonly use insulin sensitizers in the treatment of diabetes in patients with heart failure, including those who have experienced recent decompensation.7
Although the factors motivating the rapidly increasing use of insulin-sensitizing agents in patients with heart failure are not known, the effectiveness of these agents in controlling hyperglycemia may play a major role.10–14 It is frequently difficult to achieve or maintain glycemic control with other oral agents, and many patients are reluctant to accept the inconvenience and discomfort associated with insulin therapy. Metformin and the thiazolidinediones have therefore significantly expanded the options for optimizing glucose control in patients with type 2 diabetes.
Clinicians caring for patients with diabetes and heart failure may also believe that the evidence to support the warnings against the use of insulin sensitizers is inadequate. Although the risk of lactic acidosis with phenformin were significant, the risks with metformin appear to be much lower.15 Observational studies of metformin use in community settings that include patients at high risk have detected rates less than 9 in 10 000 patient-years of treatment.16 In the present study, metformin prescription was not associated with significantly higher rates of admission for metabolic acidosis, which suggests a low risk of adverse events even in this high-risk population.
Similarly, the evidence of harm from thiazolidinediones is limited. Although thiazolidinedione use may be associated with an increase in the incidence of heart failure17 and rare cases of pulmonary edema,18 fluid retention with thiazolidinediones among patients with heart failure is not clearly related to the severity of left ventricular dysfunction, often presents with peripheral edema without pulmonary edema or jugular venous distention, and resolves promptly with drug discontinuation.19 Thiazolidinedione treatment is not associated with adverse changes in myocardial structure or function,20,21 and thiazolidinedione-induced edema may be mediated either through effects on renal sodium handling or increased vascular permeability.22 Limited data suggest that higher diuretic doses and, when necessary, discontinuation of the thiazolidinedione may allow for the safe use of these agents in patients with heart failure.19 The significantly higher prevalence of peripheral edema on presentation among patients discharged with a prescription for a thiazolidinedione, many of whom were admitted with existing treatment with thiazolidinediones and insulin, and the modestly higher risk for readmission for heart failure in this group may reflect this propensity to fluid retention. Our findings, however, suggest the possibility of reduced mortality with thiazolidinedione treatment despite the higher risk of heart failure readmission.
Insulin-sensitizing agents have other notable metabolic effects that may increase clinicians’ willingness to prescribe these drugs. Metformin, unlike insulin secretagogues, does not cause weight gain or hypoglycemia.10,23 Furthermore, metformin modestly improves lipoprotein and triglyceride levels11,24 and may reduce plasminogen activator inhibitor type 1 levels.25 The finding of a reduction in mortality with metformin treatment but not with sulfonylureas or insulin in the present study is concordant with the UK Prospective Diabetes Study (UKPDS) 34, which showed lower risks of adverse events in obese patients with diabetes treated with metformin.26
Thiazolidinediones are also associated with nonglycemic metabolic benefits, including favorable changes in lipids.12,13,27 Thiazolidinedione treatment is associated with modest blood pressure lowering,21,28 reduced carotid intima-media thickness,29 antiinflammatory effects,30 and enhanced fibrinolysis,31 endothelial function,32 and left ventricular remodeling after myocardial infarction in animal models.33 These effects provide potential mechanisms to account for lower mortality with thiazolidinedione treatment in this high-risk older population with heart failure.
Because of the observational design of the present study, differences in unmeasured factors, including markers of the severity of both diabetes and heart failure, may account in part for the findings. Although the analysis adjusted for a wide range of demographic and patient variables, including markers of heart failure severity and comorbidities, differences in the treating physicians and hospitals, and the clustering of patients within hospitals, these results could reflect the influences of unmeasured confounding, including confounding by indication. Although the results should be interpreted with caution, the magnitude of the association between the prescription of both metformin and thiazolidinediones and lower mortality and the absence of a similar association with other classes of diabetes drugs suggests that insulin sensitizers may have specific beneficial effects in high-risk patients with diabetes and heart failure, and that these benefits may outweigh the risks suggested by existing evidence.
Other aspects of the present study should also be considered. Changes in medication regimens after hospital discharge could not be identified. This misclassification, however, would bias the results toward the null. Because this was a study of older fee-for-service Medicare beneficiaries, the results may not be applicable to other populations, such as younger or ambulatory patients. It is possible that both the benefits and the risks of insulin sensitizers might be the greatest in an older hospitalized population, in which rates of mortality and readmission and the risks for adverse drug events are particularly high. Finally, we were not able to assess other important outcomes beyond mortality and readmission, such as functional status, quality of life, or exacerbations of heart failure that did not require readmission. The assessment of the impact of insulin sensitizers on these outcomes is also important and should be the focus of further study.
In conclusion, treatment with insulin-sensitizing agents of the thiazolidinedione class and metformin was not associated with an excess risk of mortality and may confer important benefits to older patients with diabetes who are hospitalized for heart failure. Although further investigation to corroborate the findings of the present study is warranted, these results suggest that current recommendations to avoid the use of these medications in this context may deprive many patients of important benefits. Further clarification of the best clinical approach to the use of insulin-sensitizing drugs, optimally with randomized clinical trials, will be important in advancing the treatment of the rapidly growing population with both diabetes and heart failure.
Dr Masoudi is supported by NIH research career award K08-AG01011. Dr Foody is supported by NIH/NIA research career award K08-AG20623 and NIA/Hartford Foundation fellowship in geriatrics. The analyses on which this publication is based were performed under contract No. 500-02-CO 01 entitled “Utilization and Quality Control Peer Review Organization for the State of Colorado,” sponsored by the Centers for Medicare & Medicaid Services, Department of Health and Human Services.
The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors assume full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Centers for Medicare & Medicaid Services, which has encouraged identification of quality-improvement projects from analysis of patterns of care, and therefore required no special funding on the part of this contractor. Ideas and contributions to the authors about experiences in engaging with issues presented are welcomed.
Dr Masoudi is a compensated speaker for AstraZeneca, Pfizer, and Takeda Pharmaceuticals, N.A., and is on an advisory board for Takeda Pharmaceuticals, N.A. Dr Inzucchi is a compensated speaker for Takeda Pharmaceuticals, N.A., and GlaxoSmithKline, is on an advisory board for Takeda Pharmaceuticals, N.A., and has received research funding from Bristol-Myers Squibb. Dr. Havranek is a compensated speaker for Takeda Pharmaceuticals, N.A., and Bristol-Myers Squibb and has received consulting fees from Bristol-Myers Squibb. Dr Foody is a compensated speaker for Merck, Pfizer, and Bristol-Myers Squibb.
Consulting Editor for this article was Burton E. Sobel, MD.
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