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Objective To review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes.
Design Systematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes.
Data sources Electronic databases, manual reference search, and contact with investigators.
Review methods Two reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate.
Results Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies.
Conclusion Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies.
Worldwide, more than 171 million people have diabetes, and its prevalence is expected to double by 2030.1 People with diabetes are at increased risk of developing heart failure,2 3 with the relative risk increasing by 10-15% per unit increase in glycated haemoglobin.4 5 6 7 Conversely, heart failure is present in 25-40% of all adults with diabetes.2 8 9 10 11 12 Moreover, people with heart failure have worse outcomes if they also have diabetes,13 14 15 and it has been suggested that any level of hyperglycaemia is associated with increased rates of hospital admission, even in patients without manifest diabetes.16
How best to achieve glycaemic control in patients with diabetes and heart failure is therefore an important clinical question. Many antidiabetic drugs are now available to control hyperglycaemia. However, their role in managing diabetes in patients with heart failure is uncertain,17 and considerable controversy exists about the overall effect of antidiabetic agents on outcomes in people with comorbid diabetes and heart failure.w1 w2 Even the level of optimal glucose control in patients with diabetes and heart failure remains uncertain, and some evidence suggests that tight glycaemic control (glycated haemoglobin ≤7%) may be associated with worse survival than less tight control in patients with heart failure, irrespective of the agent used.18 As a result, outcomes are possibly affected not only by the choice of antidiabetic agent, but also by the degree of glycaemic control achieved with the agent.
Because of the lack of evidence around these matters, current recommendations are based on pathophysiological rationale, clinical experience, and expert consensus. A better understanding of the effects of antidiabetic agents on the health of people with heart failure and diabetes is needed.17 Thus, we conducted a systematic review to examine the relation between antidiabetic treatment and outcomes in people with heart failure and diabetes.
We used a comprehensive search strategy of various electronic databases (Medline (1966-2007), HealthSTAR (1966-2007), Embase (1980-2007), Cumulative Index to Nursing and Allied Health Literature (1982-2007), International Pharmaceutical Abstracts (1970-2007), Allied and Complementary Medicine (1985-2007), Cochrane Central Register of Controlled Trials (1991-2007), and the Web of Science (1900-2007)) from their date of inception until the week of 16 July 2007 for studies with contemporaneous comparison groups (such as randomised controlled trials or cohort studies) that evaluated the association between antidiabetic agents and clinical outcomes of hospital admission or mortality (or both) in patients with diabetes and heart failure (appendix on www.achord.ca). In addition, we also manually searched reference lists from original studies and review articles and contacted experts and authors of included studies. The search was not restricted by language or quality of study. We did not assess the risk of developing heart failure associated with antidiabetic drugs.
Two reviewers (DTE and DFB) independently identified relevant citations and included them if they described original research, included subjects with both diabetes and heart failure, evaluated the effects of antidiabetic agents on health outcomes (mortality, all cause hospital admission, and hospital admission for heart failure), and included a contemporaneous control group for comparison. Discrepancies were resolved by consensus after review by a third investigator (JAJ). All data were extracted and DTE and DFB independently assessed the methodological quality of included studies using a validated quality checklist.19 The maximum score on the quality checklist is 32, with a score of 12 (38%) or greater considered to be acceptable quality.19 20
To summarise the effects of antidiabetic drugs on outcomes of interest (all cause mortality or hospital admission), we abstracted the risk estimates and 95% confidence intervals from each study. For studies with insufficient information, we contacted the primary study authors to acquire and verify data where possible. If appropriate, we then pooled data across studies using random effects models if excessive statistical heterogeneity did not exist (measured using the I2 statistic and defined a priori as P≤0.10 or I2≥50%).21 We used Cochrane Review Manager 4.2 for all analyses.
Our search yielded 10091 citations, and eight studies met our inclusion criteria—one randomised controlled trial, two post hoc subgroup analyses from randomised trials, four retrospective cohort studies, and one prospective cohort study (fig 11).w1-w8 Interobserver agreement was κ=0.84 for study inclusion.
Of the eight studies, three had more than two comparison groups. As a result, four studies evaluated the effect of insulin treatment in patients with heart failure (n=9104), three examined metformin (n=3327), four evaluated thiazolidinediones (n=3409), and two studies (n=8918) compared sulfonylureas with other agents. No studies specifically evaluated the effects of alpha glucosidase inhibitors (such as acarbose and meglitol) or non-sulfonylurea insulin secretagogues (such as repaglinide and nateglinide) in patients with heart failure. The box and table 11 summarise the eight studies and their key findings. Overall, the studies were of acceptable quality, with a methodological quality score ranging from 13 (41%) to 22 (69%) (box); the median quality score was 16 (50%).
Table 22 summarises the statistical heterogeneity of the studies. A formal meta-analysis was not performed for the effects of insulin or metformin on all cause mortality because of significant statistical heterogeneity. With respect to hospital admission, meta-analyses could only be interpreted for the effects of metformin on all cause hospital admission and thiazolidinediones on hospital admission for heart failure (table 22).
Outcomes with insulin were evaluated in a subgroup analysis of 496 patients with diabetes and left ventricular dysfunction (ejection fraction <40% after acute myocardial infarction) from the survival and ventricular enlargement (SAVE) trial (box).w6 After multivariate adjustment, compared with 328 patients not treated with insulin (but treated with diet, sulfonylurea, or metformin), the 168 patients treated with insulin had significantly increased risk of all cause mortality (adjusted hazard ratio 1.66, 95% confidence interval 1.20 to 2.31), and cardiovascular morbidity (hospital admission for heart failure or prescription of an open label angiotensin converting enzyme inhibitor, or myocardial infarction) and mortality (1.38, 1.06 to 1.80; table 1).
The effect of insulin was also evaluated in the CHARM (candesartan in heart failure: assessment of reduction in mortality and morbidity) study (box).22w4 Although insulin was not directly compared with other antidiabetic drugs in adjusted analyses, unadjusted risk ratios calculated from the raw data presented in the paper suggest that treatment with insulin is associated with an increased risk of all cause mortality (risk ratio 1.25, 1.03 to1.51) and death from cardiovascular disease or hospital admission for heart failure (1.55, 1.29 to 1.86) compared with other treatments in patients with diabetes (table 1).22w4
Outcomes with insulin were also assessed in 554 consecutive patients referred to a university medical centre for management of heart failure (box).w5 Of these patients, 132 (24%) had diabetes and were prospectively followed for 11.7 months. Although insulin and non-insulin treatments were not directly compared in patients with diabetes, extrapolation from the raw data suggests an unadjusted risk ratio for all cause mortality of 3.42 (1.40 to 8.37) at one year and 2.20 (0.96 to 5.03) at two years (table 1) for patients with diabetes treated with insulin compared with those not treated with insulin.
The effects of insulin on mortality were also evaluated in a retrospective cohort study of 16417 Medicare beneficiaries with diabetes who were discharged from hospital with a primary diagnosis of heart failure (box).w1 Unlike previous studies, this study found no association between the use of insulin and mortality (adjusted hazard ratio 0.96; 0.88 to 1.05) compared with patients receiving metformin, thiazolidinediones, sulfonylureas, non-sulfonylurea insulin secretagogues, or alpha glycosidase inhibitors (table 1).w1
Outcomes with metformin were evaluated in a retrospective cohort study of Medicare beneficiaries with diabetes discharged after hospital admission for acute myocardial infarction (box).w3 Subgroup analysis of the patients with diabetes and moderate to severe impaired left ventricular systolic function (n=2875) suggested that after multivariate adjustment treatment with metformin was not associated with any risk of all cause mortality at one year compared with patients receiving sulfonylureas, non-sulfonylurea insulin secretagogues, alpha glucosidase inhibitors, and insulin (n=406; 0.92, 0.72 to 1.18; table 1).w3
The study of Medicare beneficiaries with diabetes discharged with a primary diagnosis of heart failure also evaluated the effect of metformin on all cause mortality at one year (box).w1 After multivariate adjustment, compared with patients not receiving insulin sensitisers (that is, receiving sulfonylureas, non-sulfonylurea insulin secretagogues, alpha glucosidase inhibitors, or insulin) (n=12069), all cause mortality was significantly lower in patients treated with metformin (n=1861; 0.86, 0.78 to 0.97), as well as in patients treated both with metformin and thiazolidinediones (n=261; 0.76, 0.58 to 0.99; table 1). In addition, no difference was seen in the risk for all cause hospital readmissions for patients receiving metformin (0.94, 0.89 to 1.01) and a lower risk was seen in patients treated with both metformin and thiazolidinediones (0.82, 0.69 to 0.96; table 1). A lower risk was also seen for metformin users with respect to readmissions related to heart failure (0.92, 0.86 to 0.99) and a trend towards reduction in patients receiving both metformin and thiazolidinediones (0.85, 0.71 to 1.01).
In a retrospective analysis using administrative records, another study compared metformin alone, or combined with sulfonylurea, to sulfonylurea monotherapy in 1833 patients with newly treated diabetes and incident heart failure (box).w2 After multivariate adjustment, all cause mortality was significantly lower with metformin monotherapy (0.66, 0.44 to 0.97 at one year; 0.70, 0.54 to 0.91 after 2.5 years), or with combined treatment with metformin-sulfonylurea (0.54, 0.42 to 0.70 at one year; 0.61, 0.52 to 0.72 after 2.5 years; table 1). A reduction in the composite outcome of all cause mortality or hospital admission was also seen at the end of follow-up for the metformin monotherapy group (0.83, 0.70 to 0.99) and for combination therapy (0.86, 0.77 to 0.96; table 1).
Both of the studies assessing the effect of metformin on all cause hospital admission at one year were of good methodological quality (box) and yielded similar effect estimates.w1,w2 The pooled effect suggests that treatment with metformin may be associated with reduced all cause hospital admission at one year compared to other treatments (pooled odds ratio 0.85, 0.76 to 0.95; I2=21%; P=0.004; fig 22).
In the previous Medicare study of patients with diabetes discharged after hospital admission for acute myocardial infarction,w3 after multivariate adjustment, the risk of all cause mortality at one year was no different for patients who received thiazolidinediones (n=255) than for patients treated with sulfonylureas, non-sulfonylurea insulin secretagogues, alpha glucosidase inhibitors, or insulin (1.04, 0.83 to 1.31; table 1). There was a trend, however, towards an increased risk of readmission for heart failure associated with thiazolidinediones (n=255; 1.15, 0.97 to 1.38).w3
In the second Medicare study of patients with diabetes discharged with a primary diagnosis of heart failure, after multivariate adjustment as above (n=12069), all cause mortality at one year was significantly lower for patients treated with thiazolidinediones (n=2226; 0.87, 0.80 to 0.94; table 1).w1 This study also found no difference in the risk for all cause hospital readmissions for patients receiving thiazolidinediones (1.04, 0.99 to 1.10). However, a small increased risk of readmission for heart failure was seen in patients receiving thiazolidinediones (1.06, 1.00 to 1.12).
In a retrospective cohort study of ambulatory patients followed through Veteran Affairs medical centres (box), after multivariate adjustment no differences were seen in all cause mortality at two years (n=814; 0.98, 0.81 to 1.17) or in hospital admission for heart failure (1.00, 0.81 to 1.24; table 1) in patients treated with thiazolidinediones compared with those not receiving insulin sensitisers (n=4700). However, in patients not receiving insulin, thiazolidinediones (n=381) were associated with an increased risk of hospital admission for heart failure compared with those not receiving insulin sensitisers (n=2217; 1.62, 1.15 to 2.29).w8
The only randomised controlled trial evaluated the addition of rosiglitazone (n=110) or placebo (n=114) to existing antidiabetic agents in patients with New York Heart Association class I or II disease (box).w7 Although not a specific end point of the study, after 52 weeks of treatment (compared with placebo) there was a trend towards an increased risk of all cause mortality for rosiglitazone (hazard ratio 1.50, 0.49 to 4.59) and in the proportion of patients with hospital admission for heart failure (relative risk 1.30, 0.35 to 4.82; table 2). A trend towards an increase in all cause mortality or worsening heart failure was also seen (hazards ratio 1.28, 0.51 to 3.21.
The pooled effect of the four studies which assessed the effect of thiazolidinediones on all cause mortalityw1 w3 w7 w8 suggests that treatment with thiazolidinediones may be associated with reduced all cause mortality compared with other treatments (pooled odds ratio 0.83, 0.71 to 0.97; I2=52%; P=0.10), although moderate heterogeneity was observed (fig 33).). Similarly, the pooled effect on hospital admission for heart failure suggests that thiazolidinediones may be associated with an increased risk of such admission compared with other treatments (1.13; 1.04 to 1.22; I2=0%; P=0.004; fig 44).w1 w3 w7 w8 All studies evaluating treatment with thiazolidinediones were of good methodological quality (box).w1 w3 w7 w8 For all cause mortality, although the size and direction of effect estimates varied among studies, we found no consistent pattern of effect in relation to study quality. Similar effect estimates were seen for all studies regardless of quality with respect to hospital admission for heart failure.
Few studies formally evaluated treatment with sulfonylureas as an independent exposure group. In the studies evaluating other oral treatments, however, sulfonylureas were used in about 55% of all patients in the main comparator groups (n≈11000). As a result, treatment with sulfonylurea was well represented in all of the studies evaluating oral antidiabetic agents included in our review.
Apart from the effect of sulfonylureas relative to metformin use already mentioned,w2 only one other study looked at sulfonylureas.w1 After multivariate analysis, no increased risk of mortality at one year was seen for patients receiving sulfonylureas compared with patients receiving other insulin secretagogues, alpha glucosidase inhibitors, metformin, thiazolidinediones, or insulin (0.99; 0.91 to 1.08).
Heart failure is a common comorbidity in patients with diabetes. Despite the high morbidity and mortality associated with the disease, our systematic review found few studies that formally compared antidiabetic drugs in this important population. Although several studies have evaluated the incidence of heart failure associated with the use of various antidiabetic agents,3 8 23 24 25 26 our review focused solely on the impact of such treatments in people with comorbid heart failure and diabetes. Of the eight studies included in this review, most studies were observational and there was only one randomised controlled trial, which was not designed to evaluate clinical outcomes. All studies were published in the past two years, and focused on use of insulin, thiazolidinediones, or metformin.
In the four studies that specifically evaluated the use of insulin treatment, three suggested an increase in mortality, and one reported no association with mortality. Statistical heterogeneity precluded formal meta-analysis. Importantly, in two of the studies reporting increased mortality, there was no multivariate adjustment for the comparison between insulin and non-insulin treatments in patients with diabetes. Furthermore, none of the studies randomised patients to insulin or non-insulin treatment. As a result, it is difficult to tell whether this is a true adverse effect of insulin or whether it is simply confounding by indication. Treatment with insulin in these studies may well have been a marker for more advanced diabetes or vascular disease (or both).w6 Thus, treatment with insulin may not, in itself, be associated with an increase in adverse effects in this population. Indeed, in one study that adjusted extensively for clinically important variables and compared insulin with other antidiabetic agents, insulin was not associated with an increased risk of mortality.w1
Historically, metformin has been considered absolutely contraindicated in patients with heart failure who need drug treatment because of concerns about lactic acidosis. Recently, however, the US Food and Drug Administration has removed the heart failure contraindication from the packaging of metformin (Glucophage and Glucophage XR), although a strong warning for the cautious use of metformin in this population still exists.27 The true prevalence of metformin use in patients with heart failure is not known, but published studies suggest 10-25% of patients receiving metformin have comorbid heart failure.28 29 30 Despite the concerns, our analysis revealed that treatment with metformin may be associated with lower mortality rates, although statistical heterogeneity precluded formal meta-analysis. Furthermore, no study found an increase in adverse events with metformin and the results of both studies that evaluated all cause hospital admissions in metformin users suggested that this drug is associated with a lower rate of all cause hospital admission than other antidiabetic drugs.
Thiazolidinediones are also relatively contraindicated in patients with New York Heart Association class III or IV disease because of concerns about fluid retention, which may worsen symptoms of heart failure.31 Yet, the pooled effects for mortality suggest that thiazolidinediones may be associated with reduced mortality, although the results should be interpreted cautiously as moderate statistical heterogeneity was present. The only randomised controlled trial showed a trend towards an increased risk of mortality with thiazolidinediones; however, the study was not specifically designed to assess clinical outcomes and 62 (28%) patients withdrew from the study.w7 As a result, the study was underpowered to detect any differences in clinical outcomes between treatment groups. Data from one of the two large observational studies suggest that thiazolidinediones may be associated with lower mortality, whereas this was not seen in the other study.w1 w8 This discrepancy may be related to the lower severity of illness in the patients in the second study, the under-representation of female patients, or differences in the use of combination treatment between study groups.w8
All studies except for one reported higher numbers of hospital admissions related to heart failure for patients receiving thiazolidinedionesw1 w3 w7 w8 ; this risk was confirmed by formal pooling of the data. This is consistent with evidence from randomised controlled trials, including the recently published interim analysis of the RECORD (rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes) study, which has consistently shown increased fluid retention and admission for heart failure in patients without pre-existing heart failure who use thiazolidinediones.26 32 33 34 Recently, the US Food and Drug Administration has changed the package labels for thiazolidinediones to include a “black box” warning emphasising that these drugs may cause or exacerbate heart failure in certain patients. Furthermore, given the recent controversy over the use of thiazolidinediones and increased risk of myocardial infarction,35 the overall impact on health remains uncertain.36
Although the lower mortality rates associated with use of metformin or thiazolidinediones are consistent with those seen in randomised controlled trials of insulin sensitisers in other populations with diabetes,26 32 37 none of the three included studies were randomised controlled trials. Although a wide range of demographic factors and patient characteristics were adjusted for in the studies, the study groups may have differed in severity of diabetes, heart failure, or other cardiovascular risk factors. Specifically, because of the commonly perceived risks of insulin sensitisers, these drugs may have been used preferentially in patients thought to be at lower risk than those given other treatments. Thus, the benefits of metformin and thiazolidinediones on mortality may be due to selection bias in these studies. Furthermore, only one study specifically evaluated the effects of oral antidiabetic agents as monotherapy.w2 Contamination of comparison groups as a result of the use of multiple antidiabetic drugs is a possibility in the other two studies.w1 w3
Only two studies specifically evaluated sulfonylureas as an independent exposure.w1 w2 One study found that sulfonylurea monotherapy may be associated with worse outcomes, w2 whereas the other did not.w1 The discrepancy may partly be due to the comparator groups used in the studies. The first study compared sulfonylurea monotherapy with metformin, which has been shown to be beneficial in all similar studies, while the second compared sulfonylurea exposure (alone or in combination) with treatments that did not specifically include metformin. In the first study, it is not clear whether the risk estimates were a result of an adverse effect of sulfonylureas, a beneficial effect of metformin, or confounding by indication. Although these results are consistent with other studies evaluating sulfonylureas,37 38 39 40 a recent meta-analysis has indicated that these drugs are not associated with an increase in cardiovascular events.41 Given the current controversy surrounding the use of sulfonylureas in patients with pre-existing cardiovascular disease,42 more research is needed to determine the true impact of these drugs in people with diabetes and heart failure.
Inherent to any systematic review is the potential for publication or selection bias. Studies that may have evaluated the use of antidiabetic agents in patients with heart failure as part of a stratified or secondary analysis may not have been identified using standard search strategies. However, manual searches and contact with primary authors of the included studies provided no extra articles. Any relevant articles are therefore unlikely to have been missed. Secondly, the included studies were mainly observational and only one study randomised patients to different antidiabetic drugs. As a result, the effects of unmeasured confounding variables could not be fully explored and this may be a limitation of most of the reported studies.
Our results suggest that of the current antidiabetic agents, metformin is the only one not associated with any measurable harm in people with diabetes and heart failure and is associated with reduced mortality. Given the large number of people affected with diabetes and heart failure and the fact that this population is expected to increase rapidly, evidence on how to optimally control glycaemic levels in this population is urgently needed. It is therefore imperative that research be undertaken to determine the optimal approach for glycaemic control in patients with heart failure. Ideally, this research should be a randomised controlled trial which includes the use of metformin or thiazolidinedione in patients with heart failure and diabetes. Furthermore, this trial should be aimed at evaluating the effect of these treatments on glycaemic control and its relation to long term outcomes, as well as the effect of these treatments on morbidity and mortality in people with heart failure and diabetes.
Web references w1-w8 are on bmj.com
Contributors: DTE, FAM, DFB, SRM, RTT, and JAJ helped plan and design the study. DTE, DFB, JV, and JAJ collected the data. DTE conducted the statistical analyses. All authors had access to the data and helped interpret the data. DTE wrote the first draft of the paper. All authors reviewed and revised the paper for important intellectual content and approved the version. DTE led the study, is lead author, and is guarantor.
Funding: DTE held a doctoral research award with Canadian Institutes for Health Research (CIHR). SRM and FAM are new investigators with CIHR and are population health investigators with the Alberta Heritage Foundation for Medical Research (AHFMR). FAM and RTT hold the Merck Frosst/Aventis chair in patient health management. JAJ holds a Canada Research chair in diabetes health outcomes, is a health scholar supported by AHFMR, and 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). The study sponsors played no role in study design or conduct; collection, analysis, interpretation of data; writing of the report; or in the decision to submit the paper for publication.
Competing interests: None declared.
Ethical approval: Not required.