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European Journal of Heart Failure 2008 10(7):703-708; doi:10.1016/j.ejheart.2008.05.013
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© 2008 European Society of Cardiology

The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy

Finlay A. McAlistera,*, Dean T. Eurichb, Sumit R. Majumdara and Jeffrey A. Johnsonb

a Division of General Internal Medicine, Department of Medicine, University of Alberta Edmonton, Alberta, Canada
b School of Public Health, University of Alberta Edmonton, Alberta, Canada

* Corresponding author. 2E3.24 WMC, University of Alberta Hospital, 8440 112 Street, Edmonton, Alberta, Canada T6G 2R7. Tel.: +1 780 407 1657; fax: +1 780 407 2680. E-mail address: Finlay.McAlister{at}ualberta.ca (F.A. McAlister).


   Abstract
Top
 Abstract
1. Introduction
 2. Subjects, materials, and...
 3. Results
 4. Discussion
 References
 
Aim: To determine if the risk of developing heart failure (HF) is associated with the use of sulfonylurea or metformin in patients with diabetes.

Methods: Retrospective cohort study of all adults without HF newly treated with oral antidiabetic drugs in Saskatchewan, Canada between 1991 and 1999.

Results: Of 5631 diabetic subjects (mean age 66±13years) newly treated with a single oral agent and followed for 4.7 (±2.2) years, 981 developed HF (4.1 cases per 100 patient years). The incidence of HF was greater in patients using sulfonylurea monotherapy (4.4 cases per 100 treatment years) than those taking metformin monotherapy (3.3 cases per 100 years), and users of high-dose sulfonylureas were more likely to develop incident HF than users of high-dose metformin (adjusted HR 1.24, 95% CI 1.01–1.54). Users of high-dose sulfonylureas were also more likely to develop HF (HR 1.38, 95% CI 1.20–1.60) than users of low-dose sulfonylureas; no such association existed for metformin users (HR 1.06, 95% CI 0.81–1.41).

Conclusions: Users of higher doses of sulfonylurea exhibited a greater risk of developing HF. Clinicians should carefully weigh the need for high-dose sulfonylurea therapy in diabetic subjects with, or at high risk of, HF.

Key Words: Sulfonylurea • Metformin • Dose–response relationship • Diabetes • Heart failure

Received November 28, 2007; Revised May 22, 2008; Accepted May 22, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Subjects, materials, and...
 3. Results
 4. Discussion
 References
 
Heart failure (HF) commonly develops in patients with type 2 diabetes [1]. In fact, the annual incidence rates have been reported to range from 3% in unselected patients (average age 63 years) [2] to 13% in elderly patients (average age 74 years) [3]. Although thiazolidinediones have been shown to be associated with increased fluid retention and risk of developing HF [4-7], it is uncertain whether other oral antidiabetic drugs predispose patients to develop HF or not. Only 50 cases of HF occurred during 4 years of follow-up in the Diabetes Outcome Progression Trial (in which patients were randomised to sulfonylurea, metformin, or thiazolidinedione) [8] and cohort studies have reported inconsistent effects of one oral drug class compared to others [9,10].

Demonstration that a particular drug class increased or decreased the risk of incident HF or exhibited a dose-response gradient [11] for risk of heart failure would contribute further evidence to the debate about which antidiabetic drug class is most appropriate for patients with type 2 diabetes at risk for HF.


   2. Subjects, materials, and methods
Top
 Abstract
 1. Introduction
 2. Subjects, materials, and...
3. Results
 4. Discussion
 References
 
2.1. Data sources
We conducted this retrospective inception cohort study using the computerized databases of Saskatchewan Health which are linkable, contain data on 99% of the approximately 1 million residents of the province of Saskatchewan who are covered under the universal health care plan of Saskatchewan, and have been used in numerous pharmacoepidemiologic studies [12,13]. The Saskatchewan Health databases include demographic and vital statistics, outpatient prescription drugs for all registrants (i.e. not just those over age 65 like many administrative databases), information on all hospitalisations (with International Classification of Disease, 9th revision (ICD-9) diagnostic codes for the primary/most responsible diagnosis and up to 15 secondary diagnoses for each hospitalisation), and outpatient physician services (with ICD-9 diagnostic codes up to three digits for each visit) for this population.

Institutional approval for this study was obtained from the Health Research Ethics Board of the University of Alberta.

2.2. Definition of cohort
For this study, we selected those Saskatchewan Health beneficiaries eligible for prescription drug benefits who received at least one new prescription for an oral antidiabetic medication between January 1 1991 and December 31 1996, who were aged 30 years or older, who had at least 1 year of continuous coverage in the provincial health plan, who were not treated with insulin, and who did not have a diagnosis of HF at baseline (defined as those with a hospitalisation for heart failure (ICD-9 code 428) as a primary or secondary diagnosis in the 3 years prior to starting their first oral antidiabetic agent) [14,15]. As "combination oral therapy" could include patients who were started on one drug and then had another drug added at a later time, as well as those who were switched from one drug to another at any time during follow-up, we excluded any patients receiving "combination therapy" from our analyses of HF incidence due to the potential for immortal time bias in the combination therapy group (i.e. those patients who live longer without developing HF would be more likely to eventually receive more than one agent than those patients who develop HF early, thus leading to a spurious apparent association between using more than one drug and a reduced incidence of HF) [16].

Thus, our study sample consisted of 5631 adults with recent onset diabetes who were treated with monotherapy using an oral antidiabetic agent ("new-user design"), none of whom had a prior diagnosis of HF [17]. All subjects were followed from their index drug dispensation date until termination of Saskatchewan Health coverage, death, or December 31, 1999, providing a maximum follow-up of 9 years.

2.3. Definition of exposure
We classified these patients into three groups based on their medication dispensation histories: subjects dispensed sulfonylureas exclusively during the entire duration of this study (sulfonylurea monotherapy), subjects dispensed metformin exclusively during the entire duration of this study (metformin monotherapy), and subjects dispensed combination therapy at any point during follow-up. As mentioned in the paragraph above, we excluded those patients receiving combination therapy from further analyses to minimize the risk of immortal time bias. Thus, both monotherapy groups included those subjects who received monotherapy with that agent from the beginning of the study until the end of the study or until they developed HF. We stratified each of the monotherapy groups by level of exposure to prescribed therapy (using average daily dose prior to the development of HF or end of follow-up as the measure of exposure). To determine the average daily dose each subject was exposed to, we divided the total amount of active agent dispensed by the subject's duration of follow-up (with those patients who developed HF censored at the time of HF diagnosis) and stratified patients as "higher dose" or "lower dose" relative to the median daily dose for that group as per an earlier study [18].

2.4. Outcomes and analyses
We classified a patient as having developed HF if they had a primary, most responsible, or secondary diagnosis of HF (ICD 9 code 428.x) during a hospitalisation or outpatient physician visit. We used Chi-square and Student's T-test or Kruskal-Wallis tests where appropriate to compare baseline characteristics between monotherapy treatment groups, and Kaplan-Meier analysis to examine unadjusted survival patterns across study groups.

To examine whether the incidence of heart failure differed by oral antidiabetic agent, we calculated the incidence rate for patients using metformin monotherapy or sulfonylurea monotherapy. Using Cox proportional hazards regression models, we calculated unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) to assess the relationship between antidiabetic drug use and timing/occurrence of incident HF. Potential confounding variables included were age, gender, the modified Chronic Disease Score (CDS) [19-21], therapies known to affect heart failure occurrence (ACE inhibitors or angiotensin II receptor blockers or beta-blockers) or strongly correlated with factors predicting HF (for example, short acting nitrates as a marker for coronary artery disease), and total physician visits after diabetic medication index dispensation but prior to HF diagnosis (as a proxy for duration and severity of diabetes) — with the exception of beta-blockers, all of these covariates were confirmed to be associated with the development of HF on multivariate logistic regression. The CDS provides an indication of burden of concurrent comorbidities by identifying specific drug therapies during the follow-up period and has performance metrics similar to other comorbidity indices in patients with diabetes [19-21].

To examine for dose-response gradients, we constructed separate multivariate models for each monotherapy group. Subjects with the lowest level of exposure (i.e. "lower daily dose") served as the reference group for each HR reported. The same covariates as described earlier were included in each model and to adjust for potential selection bias ("confounding by indication") we also calculated a propensity score to represent the likelihood of receiving a higher dose of antidiabetic drug, given the individual's characteristics using standard methods and included this as a covariate in all multivariate models. The inclusion of the propensity score in the analysis made no significant difference in the HR point estimates obtained (i.e. <1% change in point estimates) nor the width of confidence intervals, and because our findings were unchanged we present models without propensity scores. Proportionality assumptions for the Cox model were tested with both the log-minus-log tests and extended Cox models and met for all analyses. All first-order interaction terms were tested in these models; as none had p values <0.10, none was included in our final models. All analyses were conducted using SPSS version 14.


   3. Results
Top
 Abstract
 1. Introduction
 2. Subjects, materials, and...
 3. Results
4. Discussion
 References
 
The 5631 new users of oral antidiabetic agent monotherapy who did not have HF at baseline in our study were treated with sulfonylurea monotherapy throughout the entire follow-up period (n=4162, 17 735 person-years follow-up) or metformin monotherapy throughout the entire follow-up (n=1469, 6270 person-years follow-up). Mean age of subjects was 65.8 (±13.3) years, 57% were male, and the median burden of chronic diseases, estimated by the CDS, was 8. Sulfonylurea monotherapy users were older, more likely to be male, and less likely to be treated with ACE inhibitors (Table 1). Overall, 96% of sulfonylurea monotherapy used glyburide exclusively.


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  		Table 1 Characteristics of 5631 individuals with type 2 diabetes who did not have heart failure and were newly treated with oral agent monotherapy

 
During 4.65 (±2.16) years of follow-up, 981 (17.4%) patients developed HF (4.1 incident cases per 100 patient years) — 773 of the patients receiving sulfonylurea monotherapy and 208 of the patients receiving metformin monotherapy. Predictors of developing HF on multivariate analysis included older age, male sex, greater comorbidity, and nitrate use; use of ACE inhibitors or ARBs was associated with a lower risk of developing HF (Table 2). Although the incidence of HF was higher (Fig. 1, unadjusted HR 1.32, 95% CI 1.13-1.54, p<0.001) in those patients taking sulfonylurea (18.6% or 4.4 cases per 100 patient years of monotherapy) than those taking metformin monotherapy (14.2% or 3.3 cases per 100 patient years), after adjusting for baseline differences in the covariates described in Table 2, patients treated with sulfonylureas were not more likely to develop HF than those treated with metformin (adjusted HR 1.16, 95% CI 0.96-1.41). However, users of high-dose sulfonylureas were more likely to develop incident HF than users of high-dose metformin, even after adjusting for the covariates in Table 2 (adjusted HR 1.24, 95% CI 1.01-1.54).


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  		Table 2 Predictors of developing heart failure on multivariate analysis in 5631 patients newly treated for diabetes

 


Figure 01
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  		Fig. 1 Unadjusted Kaplan-Meier analysis of heart failure incidence in patients with type 2 diabetes mellitus, by treatment category. Legend: vrecto Sulfonylurea monotherapy. vrecto Metformin monotherapy.

 
Sulfonylurea monotherapy users exposed to higher daily doses (i.e. higher than the median daily dose of 4 mg for glyburide, 198 mg for chlorpropamide, and 425 mg for tolbutamide) were more likely to develop incident HF than those patients using lower daily doses (i.e. lower than the median daily dose) of sulfonylurea, and this association persisted after adjusting for the covariates in Table 2 (adjusted HR 1.38, 95% CI 1.20-1.60, Fig. 2). A similar dosage gradient was not observed in the risk of developing HF for users of high-dose (i.e. greater than median daily dose of 726 mg) versus low-dose metformin monotherapy (adjusted HR 1.06, 95% CI 0.81-1.41, Fig. 2).


Figure 02
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  		Fig. 2 Risk of incident heart failure in 5631 individuals with type 2 diabetes treated with higher versus lower doses of monotherapy throughout follow-up. Legend: The upper half of this Forest plot presents data comparing the risk of incident heart failure in patients receiving high-dose sulfonylurea monotherapy versus the risk in those receiving low-dose sulfonylurea monotherapy while the lower half of this Forest plot presents data comparing the risk of incident heart failure in patients receiving high-dose metformin monotherapy versus the risk in those receiving low-dose metformin monotherapy. For the comparison between sulfonylurea monotherapy users and metformin monotherapy users see Fig. 1 and text of the Results section.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Subjects, materials, and...
 3. Results
 4. Discussion
References
 
This study builds on observations from previous analyses of oral antidiabetic therapy and the risk of heart failure in diabetic individuals in three important ways.

First, the frequency of HF which we observed is consistent with prior estimates in the literature for population-based samples of patients with type 2 diabetes [2] and we have confirmed the results of an earlier cohort study which suggested that the incidence of HF does not differ across oral antidiabetic drug classes [9].

Second, although we do not have access to laboratory results in our cohort, our observation that patients requiring higher doses of sulfonylurea were more likely to develop HF is consistent with other studies demonstrating that poorer glycaemic control is associated with a higher incidence of HF, both in patients with and without known diabetes [2,22-26]. A number of theories have been advanced for this finding, including a greater burden of comorbidities, higher levels of glycosylation end products, impaired endothelial function in the microvasculature, increased circulating free fatty acids, and hyperinsulinaemia (with resultant activation of the sympathetic nervous system) in patients with higher glucose levels [27].

Third, and most importantly, our finding of an adverse dose-response relationship in sulfonylurea monotherapy users but not metformin monotherapy users should raise caution in the minds of clinicians about the use of high-dose sulfonylureas in patients at high risk for HF. In addition to the potential neurohormonal effects of hyperinsulinaemia mentioned earlier (sulfonylureas are insulin secretagogues), studies in animals and man have demonstrated that sulfonylureas can reduce ischaemic preconditioning by blocking ATP-sensitive potassium channels in myocytes and thereby predispose to development of HF [28-32]. However, while numerous observational studies [12,33-35] and one large randomised trial [36] have suggested adverse cardiovascular effects with sulfonylureas compared to other oral antidiabetic agents, two other randomised trials [8,37] did not. Thus, further study (in particular a head-to-head randomised trial to compare outcomes - beyond merely glycaemic control - with various oral antidiabetic agents in diabetic individuals at high risk for HF) is clearly needed.

Although we employed a new-user design (and thus controlled for duration of diabetes in our inception cohort by enrolling subjects at the time of their first prescription for an oral antidiabetic agent) and report data from a relatively large cohort of unselected patients with type 2 diabetes who were never treated with insulin, there are several limitations to this study that should be noted. First, this study was observational and retrospective — as discussed above, a randomised trial is needed to establish, or refute, our findings since there are a number of unmeasured confounders which could have contributed to our observed associations (for example, providers who prescribe metformin may systematically differ from those who prescribe sulfonylureas in their approach to other cardiovascular risk factors, although our propensity score analyses did not uncover evidence of this). Second, our observations are based on administrative databases and as such we do not have detailed clinical information on items such as serum creatinine or severity of diabetes at baseline, body mass index, nor glycaemic control over time. Third, we relied on administrative claims to identify cases of HF. Although the use of ICD-9 code 428 to identify patients with HF has been confirmed to have an accuracy of over 95% on chart audits [14], it is impossible to distinguish diastolic from systolic HF, judge the severity of HF, nor detect patients with asymptomatic left ventricular dysfunction using administrative databases. Indeed, any under-recognition of HF by the clinicians in our study or any misdiagnosis of asymptomatic patients with left ventricular systolic dysfunction as not having HF is likely to have reduced our ability to detect a difference between drug classes. Fourth, our dataset predated the availability of the thiazolidinediones, acarbose, repaglinide, sitagliptin, or exenatide — future studies should examine for differences in HF incidence and outcomes with each of these classes.

In conclusion, we observed a greater risk of incident HF in patients treated with high-dose sulfonylurea monotherapy and a dose-response relationship between sulfonylurea exposure and risk of developing HF in patients with type 2 diabetes. These findings are of concern, since sulfonylureas are the most commonly prescribed oral antidiabetic drug in patients with type 2 diabetes [9,33,34]. While a head-to-head randomised trial to compare outcomes (beyond merely glycaemic control) with various oral antidiabetic agents in diabetic individuals at risk for HF should be a research priority, in the interim we believe that clinicians should carefully weigh the need for high-dose sulfonylurea therapy in diabetic subjects at risk of heart failure.


   Acknowledgements
 
This study was funded in part by grants from the Institute of Health Economics and the Alberta Heritage Foundation for Medical Research (AHFMR). These study sponsors did not play any role in study design or conduct; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the paper for publication.

Drs. McAlister, Eurich, Majumdar, and Johnston all receive salary support from the Alberta Heritage Foundation for Medical Research (AHFMR). Drs. McAlister and Majumdar are also supported by salary awards from the Canadian Institutes of Health Research (CIHR). Dr. McAlister holds the University of Alberta/Merck Frosst/Aventis Chair in Patient Health Management and Dr. Johnson holds a Canada Research Chair in Diabetes Health Outcomes. Dr. Johnson is Chair of a New Emerging Team (NET) grant to the Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD). The ACHORD NET grant is sponsored by the Canadian Diabetes Association, the Heart and Stroke Foundation of Canada, The Kidney Foundation of Canada, the CIHR — Institute of Nutrition, Metabolism and Diabetes and the CIHR — Institute of Circulatory and Respiratory Health.

This study is based, in part, on de-identified data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.


   References
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 Abstract
 1. Introduction
 2. Subjects, materials, and...
 3. Results
 4. Discussion
 References
 

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