Impact of metformin on the all-cause mortality of diabetic patients hospitalized with acute heart failure: An observational study using acute heart failure registry data

doi:10.21203/rs.3.rs-3103721/v1

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Impact of metformin on the all-cause mortality of diabetic patients hospitalized with acute heart failure: An observational study using acute heart failure registry data

https://doi.org/10.21203/rs.3.rs-3103721/v1

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Background

Although the hypothesis that metformin is beneficial for patients with diabetes and heart failure (HF) has been steadily raised, there is limited data on metformin use in patients with acute HF. We investigated the impact of metformin on all-cause mortality in hospitalized patients with type 2 diabetes and acute HF.

Methods

The Korean Acute Heart Failure registry enrolled patients hospitalized for acute HF from 2011 to 2014. Among this cohort, we analyzed patients with diabetes with baseline estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73m² or more. We retrospectively investigated the all-cause mortality at 1 year after discharge. Inverse probability treatment weighting method was used to adjust baseline differences on metformin treatment.

Results

The study analyzed data from 1,309 patients with diabetes (mean age 69 years, 56% male). Among them, 613 (47%) patients were on metformin. During the median follow-up period of 11 months, 132 (19%) and 74 (12%) patients not receiving and receiving metformin treatment died, respectively. The all-cause mortality rate was lower in metformin users than in non-users (hazard ratio 0.616 [0.464–0.819], P < 0.001). HF readmission rate was not significantly different. After adjustment, metformin was significantly associated with a lower risk for all-cause mortality (hazard ratio 0.677 [0.495–0.928], P-value = 0.015). In subgroup analyses, this association remains significant irrespective of baseline kidney function (eGFR < 60 or ≥ 60 ml/min/1.73m², P-for-interaction = 0.176) or left ventricular ejection fraction (< 40%, 40–49%, or ≥ 50%, P-for-interaction = 0.224).

Conclusions

Metformin treatment at the time of admission was associated with a lower risk for 1-year all-cause mortality in patients with diabetes, hospitalized for acute HF.

acute heart failure

mortality

metformin

type 2 diabetes

Metformin is a cornerstone medication in the glucose-lowering treatment in patients with type 2 diabetes. Currently, metformin is supported by many scientific associations as a primary treatment for patients with type 2 diabetes based on glucose reduction effects, safety, favorable effects on weight, and low cost [1]. Moreover, its use was corroborated by the extensive evidence from the UK Prospective Diabetes Study (UKPDS) trial, which demonstrated long-term benefits and favorable outcome in terms of cardiovascular morbidity and mortality [2, 3]. In the UKPDS study of patients with type 2 diabetes, metformin reduced acute myocardial infarction by 39%, coronary death by 50%, and stroke by 41% over 10 years in patients with type 2 diabetes without history of cardiovascular disease [2]. Several publications have focused on the cardiovascular beneﬁts of metformin, and since 2006, a joint statement of the American Diabetes Association has recommended metformin as the initial pharmacologic treatment for type 2 diabetes until tolerated and not contraindicated [4, 5].

In terms of heart failure (HF), the presence of diabetes and insulin resistance is associated with reduced functional capacity and an increase in mortality in such patients [6, 7]. However, until the 1990s, the use of metformin for treating patients with HF or renal impairment was contraindicated due to concerns regarding the risk of lactic acidosis until the 1990s [8, 9]. Thereafter, data has been accumulated until conclusive evidence proves that the benefits of metformin use in diabetics with HF exceed the potential risk [8, 10]. Subsequently, one registry data showed that metformin therapy for diabetes in patients with advanced systolic HF was associated with improved prognosis [11], and national cohort studies from the United States and Denmark also revealed that metformin therapy was associated with lower rates of mortality in patients with diabetes and HF [12, 13]. Presently, metformin is the most frequently prescribed medication for diabetes in patients with HF with reduced ejection fraction (HFrEF), according to the CHAMP-HF registry [14]. Although the hypothesis that metformin is beneficial for diabetic patients with HF has been steadily raised, there have been no solid data on the efficacy of metformin in patients with acute HF. In this study, we aimed to investigate the impact of metformin treatment at the time of admission on all-cause mortality in hospitalized patients with diabetes and acute HF.

Data collection and study design

The Korean Acute Heart Failure (KorAHF) registry is a prospective, multicenter, cohort study designed to provide details on demographic and clinical profiles, current diagnostic approaches, treatments, and short- and long-term outcomes among patients with acute HF in the Republic of Korea. Detailed information on the study design and main results are available in previous reports (ClinicalTrial.gov NCT01389843) [15-19]. Information on patient characteristics, medical history, symptoms and signs, laboratory and echocardiographic findings, prescribed medications, invasive procedures, and outcomes were collected at admission, discharge, and follow-up.

Study participants and outcome assessment

A total of 5,625 patients who were hospitalized for acute HF from 10 tertiary hospitals throughout the country were consecutively enrolled between March 2011 and February 2014. Of the patients enrolled in the KorAHF registry, 269 patients died at the index hospitalization, and 69 patients died within one month after discharge. Patients were diagnosed with diabetes if they met any of the following criteria: use of hypoglycemic agent at the time of the index admission, HbA1c level ≥6.5% (48 mmol/mol) at baseline, random glucose level ≥200mg/dL, or hyperglycemia requiring insulin therapy during the index hospitalization. Among the 5,287 survivors at one-month post-discharge, 2,179 patients were diagnosed to have diabetes. Information on the usage and type of anti-diabetic medication was collected at the time of registry enrollment. Among the patients with diabetes, 452 patients who had significant missing data, 271 patients who had severe kidney dysfunction at baseline (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m²), and 147 patients who were on dialysis therapy at baseline, were excluded. Patients with kidney function typically has eGFR <30 ml/min/1.73 m², and thus are contraindicated against the use of metformin; these patients who are less likely to receive metformin may confound the associations between metformin and the outcomes under investigation.

The primary endpoint of the study was the all-cause mortality at 1-year post-discharge. The secondary endpoints were HF readmission and a composite of HF readmission, and all-cause mortality. The study protocol was approved by the institutional review board of each hospital. All patients provided written informed consent for participation in the registry. The present study was conducted according to the principles of the Declaration of Helsinki.

Statistical analyses

Continuous variables with normal distributions are presented as mean ± SD and were compared using the Student’s t-test or the Mann–Whitney U test when group distributions were skewed. Categorical variables were compared using the Chi-square test. The cumulative probability of events was analyzed using the Kaplan–Meier method, and the log‐rank test was used to compare the probability of event curves between the groups.

We compared the baseline characteristics between the group receiving metformin (metformin group) and those not using the medication (non-user group). Considering the confounding bias against basic clinical features, the inverse probability of treatment weighting (IPTW) method was applied and propensity score matching was performed to balance the differences in clinical features between the metformin group and the non-user group. A standardized mean difference (SMD) approach was used to evaluate the balance in covariates (SMD <0.1 was considered as negligible imbalance between groups). Pretreatment covariates included age, male sex, body mass indexes (BMI), history of atrial fibrillation, hypertension, ischemic etiology, de novo HF admission, New York Heart Association (NYHA) class III or IV at admission, systolic blood pressure at admission, baseline hemoglobin level, baseline eGFR, left-ventricular ejection fraction (LVEF), insulin therapy during hospitalization, use of sulfonylureas at admission, use of dipeptidyl peptidase-4 (DPP-4) inhibitors at admission, use of statin at admission, use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) at discharge. Restricted cubic splines were used to explore the relationship between all-cause mortality and metformin and sulfonylurea in the weighted cohort. Cox proportional hazard regression (uni-/multivariate) models were applied to estimate the association between the outcomes and groups on the IPTW dataset and subgroup analysis. In the multivariate analysis, clinically relevant variables for the study outcome were adjusted. All statistical tests were two-tailed, and a P-value <0.05 was considered significant. All analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) using the “survival”, “WeightIt”, “rms’, and “cobalt” package.

Data and Resource Availability

The data sets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Baseline characteristics

A total of 1,309 patients with HF and diabetes (mean age 69 ± 12 years, 56.1% male) were finally analyzed in this study. Among them, 613 (46.8%) patients were on metformin. Both the demographics and clinical characteristics of the patients are shown in Table 1. When comparing metformin users to non-users in this cohort, patients receiving metformin therapy had a higher BMI (24.3 vs. 23.8 kg/m², P-value = 0.013), lower rates of chronic kidney disease (defined as eGFR <60 ml/min/1.73m², 35.7 vs. 52.2%, P-value <0.001) and higher baseline eGFR levels (72.5 vs. 63.6 ml/min/1.73m², P-value <0.001). This difference reflects that metformin is less frequently used in patients with renal insufficiency in real practice. The prescription rates of sulfonylureas, DPP-4 inhibitors, and statins at admission, as well as ACEi/ARBs, and beta-blockers at discharge, were significantly higher in the metformin group than in the non-user group (Table 1). In summary, the baseline renal function and use of other diabetes drugs were significantly different according to metformin use (absolute value of SMD >0.3). After IPTW adjustment, standardized differences of weighted comparisons of all covariates were < 0.1, indicating that the distribution of baseline characteristics of patients, including baseline eGFR levels became similar between the two groups in the weighted cohort (Additional file 1: Fig. S1, Table 1). Regarding the distribution diagram of eGFR values, the eGFR levels of patients who are and are not receiving metformin after adjustment has become relatively similar than before the adjustment (Additional file 1: Fig. S2). The rationale for presenting eGFR before and after adjustment is that patients with poor kidney function are less likely to be prescribed metformin in clinical practice, as shown in Table 1.

Clinical outcomes in patients with diabetes and heart failure based on metformin therapy

During the median follow-up period of 11 months, 206 (15.7%) patients died (Table 2). All-cause mortality was lower in metformin group (n = 74) than in non-user group (n = 132) (12.1 vs. 19.0%, P-value = 0.001). Re-hospitalization events for HF was not significantly different between the two groups (25.4 vs. 25.7%, P-value = 0.962). In univariate Cox proportional hazard model, metformin use was associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.616, 95% confidence interval [CI] 0.464–0.819, P-value <0.001) (Table 3). In this analysis, other anti-diabetic drugs including insulin treatment (HR 1.128, 95% CI 0.858 – 1.484) and sulfonylurea (HR 1.068, 95% CI 0.804 – 1.42) were not significantly associated with mortality (Additional file 1: Table S1). Moreover, the Kaplan–Meier survival analysis demonstrated significantly lower mortality in the metformin group than in the non-user group (Log-rank P <0.001, Fig 1A).

Considering some differences in the baseline clinical characteristics between those treated and untreated with metformin, we created a weighted cohort with propensity score adjustment, and analyzed clinical outcomes. Patients receiving metformin were at lower risk for all-cause mortality after the double adjustments for clinical variables in the weighted cohort (HR 0.677, 95% CI 0.495–0.928, P-value = 0.015) (Table 3). Kaplan–Meier survival analysis consistently showed that patients receiving metformin were at lower risk for all-cause mortality than non-users in the weighted cohort (Log-rank P = 0.010, Fig 1B).

Impact of metformin therapy on the stratified subgroups

We performed subgroup analysis in the weighted cohort to test any heterogeneity in the treatment impact of metformin on mortality (Table 4). First, when divided into two categories based on eGFR, metformin therapy showed a significant association with low mortality in the higher eGFR groups (≥60 or ≥45 ml/min/1.73m2), but not in the lower eGFR groups. However, the differences between these groups were not statistically significant (P-for-interaction = 0.366, and 0.401, respectively). Second, we also found no significant interaction between metformin therapy and mortality rates when patients were divided into two LVEF categories (≤40% and >40%, P-for interaction = 0.175) or three LVEF categories (≤40%, 40–49%, and ≥50%, P-for-interaction = 0.224). In addition, we obtained restricted cubic splines for this interaction to test the trend of the relationship. As shown in Fig. 2, metformin has a consistently lower hazard ratio for the 1-year mortality compared to non-users across most ranges of eGFR or LVEF in the weighted cohort. In contrast, sulfonylurea was used as an indirect comparator to check the treatment effect in this cohort and the hazard ratio was not significantly different between users and non-users in most eGFR or LVEF ranges (Additional file 1: Fig. S3).

The impact of metformin therapy on other subgroups in the weighted cohort is shown in Fig. 3. The association of metformin therapy and the risk of mortality across these subgroups were presented according to age (patients aged ≥70 years or <70 years), sex (male or female patients), BMI (≥25 kg/m² or <25 kg/m²), type of admission (de novo or acute decompensated heart failure), etiology of HF (ischemic or non-ischemic), insulin therapy during the hospitalization, sulfonylurea use at baseline, baseline eGFR, and LVEF. In this analysis, there was no statistically significant difference for the association among all subgroups.

Metformin treatment at the time of admission in patients with diabetes hospitalized with acute HF were significantly associated with a lower risk of 1-year all-cause mortality compared to those not receiving metformin. This association was irrespective of the HF subtypes according to baseline kidney function or LVEF even after adjustment in weighted cohort.

Metformin treatment in type 2 diabetes

Metformin, similar to other diabetes treatments, is effective in lowering blood glucose and is often used in combination with other treatments for diabetes. The results of the UKPDS study showed the principal evidence for the effectiveness of metformin in type 2 diabetes. Patients with newly diagnosed type 2 diabetes were randomized to metformin or to diet intervention, and the treatment continued for approximately 10 years [3]. In the results, allocation to metformin was associated with statistically significant reductions in the risk of pre-specified endpoints, including myocardial infarction, any endpoint related to diabetes, and all-cause mortality [2]. Another meta-analysis examined 13 retrospective studies, which included all-cause mortality as an outcome for type 2 diabetes [20]. In this study, metformin use was associated with reduced hazard of all-cause mortality in patients with eGFR ≥30 ml/min/1.73m², but not in patients with <30 ml/min/1.73m². Therefore, our results indicate that the prognostic impact of metformin is associated with renal function and metformin is beneficial in patients with eGFR ≥30 ml/min/1.73m².

Metformin treatment in heart failure

Currently, several studies have investigated the association between metformin and the prognosis of HF. Diabetes is one of major risk factors for HF and known to be associated with poor outcome in HF [21, 22]. Roughly 40% of patients enrolled in clinical trials for HFrEF had diabetes [23], which is a similar prevalence (43%) of the KorAHF registry data [24], and had a 10% new-onset diabetes rate during a 4-year follow-up period [25]. Other studies showed the benefits of metformin in patients with HF. For example, an observational study which included 6,185 patients with HF and diabetes showed that metformin treatment reduced mortality of ambulatory patients with HF for 2 years of follow-up period (HR 0.76, 95% CI 0.63 – 0.92, P-value <0.01) [12]. This was an important issue in anti-diabetic treatment because previous studies had shown that sulfonylurea use had a higher incidence of HF [26] and risk of mortality than metformin use [27]. In addition, another study showed that metformin treatment as a monotherapy or combination therapy with other antihyperglycemic drugs or insulin had a beneficial effect on all-cause mortality (relative risk 0.37, 95% CI 0.18–0.76, P-value = 0.007) in patients with advanced systolic HF [11]. However, this study included a small number of patients (n = 401), and after multivariate adjustment, the results showed just a tendency to reduce all-cause mortality after metformin treatment compared to other antihyperglycemic drugs or insulin. A meta-analysis of about 34,000 HF patients showed that metformin was associated with reduced risk in all-cause mortality compared with other treatments (pooled adjusted risk estimate 0.80, 95% CI 0.74–0.87, P-value <0.001) [28]. However, each study constituting this meta-analysis could not reflect accurate real-world data as in our study, because their data on the used drugs in each control group, the composition of LVEF, and kidney function, were limited. Because metformin treatment is often determined by baseline renal function or LV function, it is clinically relevant to sub-analyze data on these parameters in observational studies.

Recently, the HF registry data from the United States reported that newly prescribed metformin was independently associated with reduced risk of composite of mortality and HF readmission, especially in patients with LVEF >40% [29]. Subsequently, the authors performed sensitivity analyses for the outcomes with combined previous and new users, and it showed that metformin treatment was independently associated with reduced risk of all-cause mortality. This result adds further support to our findings that prevalent metformin treatment was associated with reduced mortality among acute HF patients. Moreover, this study showed that newly prescribed sulfonylurea was associated with an increased risk of mortality alone or a composite outcome with HF readmission. Our results also showed that sulfonylurea was not associated with a mortality benefit, independent of LVEF or eGFR. Given these findings that sulfonylurea is associated with poor outcomes compared to metformin in terms of incidental HF [26, 29], it can be inferred that metformin is beneficial over sulfonylurea in patients with HF and diabetes, as addressed in the previous national cohort study [13]. Therefore, as recommended by the guideline [30], SGLT2 inhibitors should be used as first-line therapy in patients with HF with diabetes and metformin should be used rather than sulfonylurea, if clinically needed.

There was a trend of additional benefit in patients with LVEF ≤40%, but the difference was not statistically significant. This result is in line with another recent study, which showed that metformin was associated with improved outcomes in patients with HFrEF and diabetes [31]. Although the study population was small, this study also found that metformin-treated patients with HF had better glycemic profiles and improved survival compared with those who did not use metformin.

Taken together, the results of our study and others suggest that there remains some debate on which patients may benefit more from metformin based on LVEF stratification, and further studies may answer this question. Thus, we anticipate the results of the ongoing Met-HeFT [32]. This study includes patients with chronic HF in NYHA class II-IV, LVEF ≤40%, and type 2 diabetes or prediabetes (HbA1c level ≥5.5%); the patients are planned to be randomized to metformin or placebo. This study will be the first study conducted on patients with HFrEF and the largest randomized study for metformin to address clinical outcomes. Nevertheless, whether metformin shows beneficial effects even in patients with HF without diabetes remains to be clarified.

Metformin in the current era of HF with diabetes

Although the current American Diabetes Association practical guideline recommends metformin as the first-line drug for type 2 diabetes [33], recent challenges to the position of metformin stemmed from demonstrations of significant cardiovascular outcome benefits using glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors [34, 35]. The main disadvantage of metformin is that it has not been studied in a large randomized trial for cardiovascular outcome; however, metformin was positioned as a background therapy for all positive trials for new glucose-lowering agents, including SGLT2 inhibitors [1]. In a post-hoc analysis of the EMPA-REG OUTCOME trial, the risk reduction effect of empagliflozin on all-cause death in non-users of metformin was 46% vs. 22% in metformin users, although the statistical significance was marginal (P-for-interaction = 0.06) [36]. Moreover, canagliflozin from the CANVAS trial reduced the risk of cardiovascular death or hospitalization for HF by 36% in non-users of metformin but by only 12% in metformin users (P-for-interaction = 0.03) [37]. Thus, suspicions have been raised that the benefits of background metformin therapy were obscured by the effect of SGLT2 inhibitors [38]. Although current HF guidelines have established SGLT2 inhibitors as one of first line 4-pillar drugs [30], more active use of metformin should be considered, given the clinical benefit of metformin in patients with type 2 diabetes and HF, as seen in the present study. This is further emphasized by the fact that other diabetes drugs, such as sulfonylureas [26, 29] and insulin [24, 39], have not shown significant benefit and may even be harmful in HF.

Study limitations

There are several limitations that should be considered in this study. First, because this is a retrospective observational study, we cannot exclude various confounding variables or selection bias. Nevertheless, the strength of our study is that this is the result from acute HF registry data. Our multicenter registry reflects the real-world treatment behavior for acute HF and has various severity of hospitalized HF, and thus we could present the exact value of LVEF or eGFR level of study population. As mentioned in the text, the decision to use metformin is inevitably affected by the underlying kidney function in the treatment of type 2 diabetes. Therefore, we have made best efforts to adjust this bias using multivariate regression analysis in addition to IPTW with propensity score. Second, data on the use of other novel anti-diabetic drugs (e.g. SGLT2 inhibitors, GLP-1 receptor agonist) were not available. Although SGLT2 inhibitors are now well-established in the treatment of HF [40, 41], they were not yet approved for HF treatment and widely used in Korea when this study was enrolled, and thus they could not be included in the analysis. Similarly, the GLP-1 receptor agonist could not be included in the analysis. Further studies may reveal if they have any additional relationship to the effect of metformin in the treatment of HF with diabetes.

Metformin is an old drug for treatment of type 2 diabetes, and several evidence showed beneficial effect for patients with HF and type 2 diabetes. In this study, metformin treatment at the time of admission of patients with type 2 diabetes hospitalized with acute HF, were significantly associated with a lower risk of 1-year all-cause mortality compared to those not receiving metformin, irrespective of the LVEF or baseline kidney function. These findings support the use of metformin in patients with type 2 diabetes and acute HF. Thus, although SGLT2 is the first line treatment in HF with type 2 diabetes, the importance of metformin as a next step should be further emphasized.

Acknowledgement

The authors thank all participants and all investigators in the KorAHF registry.

Data Availability

The data of this study may be available on reasonable request to the Korean Acute Heart Failure.

Funding

No specific fund supports the current analysis.

Authors Contribution

All authors contributed to review and editing of the manuscript and approved the final manuscript. K-HC and JO contributed to the study design, manuscript drafting, data analysis, interpretation of data. CJL, JJP, SEL, M-SK, H-JC, J-OC, H-YL, K-KH, KHK, B-SY, D-JC, SHB, E-SJ, J-JK, M-CC, SCC, and B-HO contributed to participants recruiting in the KorAHF registry, acquisition of data. S-MK contributed to supervision and is the guarantor of this work.

Ethics approval and consent to participate

The study protocol was reviewed and approved by the institutional review board of each participating hospital. All patients provided written informed consent for participation in the registry.

Consent for publication

The authors have reviewed the manuscript and consent for publication.

Competing interests

The authors have no competing interests.

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Table 1. Baseline clinical characteristics according to the use of metformin before and after IPTW.

Variables (Total N=1,309)	Before IPTW (Original cohort)				After IPTW (Weighted cohort)
Variables (Total N=1,309)	Non-users (N=696)	Metformin users (N=613)	SMD	P -value	Non-users	Metformin users	SMD
Age, years	69.7 ± 12.3	68.9 ± 11.2	-0.071	0.196	69.6 ± 12.2	69.4 ± 11.1	-0.017
Male sex, n (%)	391 (56.2%)	344 (56.1%)	-0.001	>0.999	54.9%	54.7%	-0.004
BMI, kg/m²	23.8 ± 4.0	24.3 ± 3.7	0.138	0.013	24.1 ± 4.0	24.0 ± 3.7	-0.016
History of Atrial fibrillation, n (%)	191 (27.4%)	142 (23.2%)	-0.098	0.087	25.4%	26%	0.014
Hypertension, n (%)	476 (68.4%)	436 (71.1%)	0.059	0.311	70.4%	70.4%	-0.0002
Ischemic etiology, n (%)	359 (51.6%)	306 (49.9%)	-0.033	0.586	50.1%	49.4%	-0.012
De novo HF, n (%)	249 (35.8%)	178 (29.0%)	-0.144	0.011	33.4%	33.9%	0.009
CKD, n (%)	363 (52.2%)	219 (35.7%)	-0.335	<0.001	44.9%	44.2%	-0.015
NYHA class III/IV, n (%)	601 (86.4%)	513 (83.7%)	-0.074	0.203	85.3%	84.7%	-0.017
Systolic BP, mmHg	134.1 ± 30.2	132.6 ± 27.9	-0.050	0.357	132.9 ± 29.4	133.1 ± 28	0.008
Diastolic BP, mmHg	78.9 ± 18.4	79.6 ± 17.3	0.040	0.471	78.9 ± 18.1	79.2 ± 17.2	0.022
Pulse rate, bpm	94.0 ± 26.4	94.0 ± 25.5	0.000	>0.999	93.6 ± 25.7	93.6 ± 26	-0.001
Echocardiography
LVEF, %	37.0 ± 15.2	36.6 ± 15.0	-0.022	0.684	37.3 ± 15.2	37.1 ± 15	-0.010
LVEF ≤40%, n (%)	439 (63.1%)	393 (64.1%)	0.021	0.741	62.5%	62.8%	0.005
Laboratory findings at admission
Hemoglobin, g/dL	12.3 ± 2.3	12.6 ± 2.3	0.154	0.005	12.4 ± 2.2	12.4 ± 2.2	0.003
eGFR, ml/min/1.73m²	63.6 ± 24.4	72.5 ± 24.1	0.367	<0.001	67.7 ± 25.5	67.8 ± 24.1	0.004
Hba1c, % (n=846)	7.4 ± 1.4	7.4 ± 1.4	-0.001	0.986	7.3 ± 1.3	7.4 ± 1.5	0.072
High NP level, n (%) (n=1,175)	535 (85.2%)	437 (79.9%)	-0.140	0.02	82.3%	81.1%	-0.033
Medications at admission
Sulfonylureas, n (%)	178 (25.6%)	273 (44.5%)	0.405	<0.001	34.6%	34.5%	-0.003
Glitazones, n (%)	11 (1.6%)	15 (2.4%)	0.061	0.356	2%	2.9%	0.065
Acarboses, n (%)	66 (9.5%)	50 (8.2%)	-0.046	0.456	10.1%	7.8%	-0.079
DPP-4 inhibitors, n (%)	60 (8.6%)	123 (20.1%)	0.331	<0.001	13.9%	13.9%	-0.0005
Loop diuretics, n (%)	532 (76.4%)	451 (73.6%)	-0.066	0.258	75%	73.9%	-0.024
Thiazides, n (%)	67 (9.6%)	57 (9.3%)	-0.011	0.914	9.9%	8.4%	-0.052
Statins, n (%)	374 (53.7%)	372 (60.7%)	0.140	0.013	56.8%	57%	0.002
Treatment during hospitalization
MCS, n (%)	26 (3.7%)	24 (3.9%)	0.009	0.98	3.4%	4.7%	0.065
Insulin therapy	356 (51.1%)	216 (35.2%)	-0.325	<0.001	42.2%	42.5%	0.005
Medications at discharge
ACEi/ARBs, n (%)	489 (70.3%)	479 (78.1%)	0.180	0.001	73.3%	72.8%	-0.011
Beta-blockers, n (%)	375 (53.9%)	366 (59.7%)	0.117	0.039	57.2%	57.5%	0.005
MRAs, n (%)	365 (52.4%)	305 (49.8%)	-0.053	0.36	51.6%	51.9%	0.005

Values are mean ± standard deviation or number (%). IPTW, inverse probability treatment weighting; SMD, standardized mean difference; HF, heart failure; CKD, chronic kidney disease, defined as eGFR <60 ml/min/1.73m²; eGFR, estimated glomerular filtration rate; NYHA, New-York Heart Association; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; DPP-4 inhibitors, dipeptidyl peptidase-4 inhibitors.

Table 2. Clinical events during 1-year follow-up duration according to metformin or sulfonylurea treatment.

	Metformin non-users (N=696)	Metformin users (N=613)	P-value	Sulfonylurea non-users (N=858)	Sulfonylurea users (N=451)	P-value
Hospitalization duration (days)	8 [6 – 15]	8 [5 – 12]	0.032	8 [5 – 13]	8 [6 – 14]	0.107
HF re-hospitalization	179 (25.7%)	156 (25.4%)	0.962	215 (25.1%)	120 (26.6%)	0.587
Death	132 (19.0%)	74 (12.1%)	0.001	132 (15.4%)	74 (16.4%)	0.687

Values are median [interquartile range] or number (%).

Table 3. Univariate and multivariate Cox proportional hazard analysis for clinical events mortality according to use of metformin.

	HR	95% confidence interval	P-value
Univariate (Original cohort)
HHF	0.987	0.796 – 1.224	0.906
All-cause mortality	0.616	0.464 – 0.819	<0.001
HHF + All-cause mortality	0.885	0.739 – 1.06	0.185
Multivariate (Weighted cohort)^†
HHF	1.047	0.828 – 1.324	0.701
All-cause mortality	0.677	0.495 – 0.928	0.015
HHF + All-cause mortality	0.940	0.772 – 1.144	0.536

^†Adjusted for age, sex, BMI, de novo HF admission, NYHA class III or IV at admission, systolic blood pressure at admission, baseline eGFR at admission, baseline hemoglobin level at admission, insulin therapy during hospitalization, use of sulfonylureas at admission, use of DPP-4 inhibitors at admission, use of loop diuretics at admission, use of statins at admission, use of ACEis/ARBs at discharge, use of beta-blockers at discharge, and use of mineralocorticoid receptor antagonist at discharge.

Table 4. Multivariate Cox proportional hazard analysis for 1-year all-cause mortality according to use of metformin, stratified by eGFR and LVEF in the weighted cohort.

	Values	Number (%)	HR (95% CI)	P-value	P-for-interaction
eGFR category (1) (ml/min/1.73m²)	≥ 60	727 (55.5%)	0.521 (0.322 – 0.841)	0.007	0.176
eGFR category (1) (ml/min/1.73m²)	< 60	582 (44.5%)	0.824 (0.542 – 1.253)	0.366	0.176
eGFR category (2) (ml/min/1.73m²)	≥ 45	1031 (78.7%)	0.636 (0.441 – 0.918)	0.016	0.401
eGFR category (2) (ml/min/1.73m²)	< 45	278 (21.2%)	0.873 (0.465 – 1.639)	0.673	0.401
LVEF category (1) (%)	≤ 40	832 (63.5%)	0.578 (0.386 – 0.866)	0.007	0.175
LVEF category (1) (%)	> 40	477 (36.4%)	0.873 (0.530 – 1.440)	0.596	0.175
LVEF category (2) (%)	≤ 40	832 (63.5%)	0.578 (0.386 – 0.866)	0.007	0.224
	40 – 50	190 (14.5%)	0.775 (0.261 – 2.305)	0.647
	≥ 50	287 (21.9%)	0.981 (0.535 – 1.799)	0.949

Adjusted for age, sex, BMI, de novo HF admission, NYHA class III or IV at admission, systolic blood pressure at admission, baseline eGFR at admission, baseline hemoglobin level at admission, insulin therapy during hospitalization, use of sulfonylureas at admission, use of DPP-4 inhibitors at admission, use of loop diuretics at admission, use of statins at admission, use of ACEis/ARBs at discharge, use of beta-blockers at discharge, and use of mineralocorticoid receptor antagonist at discharge.

No competing interests reported.

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Impact of metformin on the all-cause mortality of diabetic patients hospitalized with acute heart failure: An observational study using acute heart failure registry data

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