Based on previous basic and clinical studies, we hypothesised that metformin administration would confer cardioprotection in the setting of AMI. We interrogated linked, prospectively recorded, electronic health records of patients with T2DM experiencing their first AMI, using primary care linked to hospital admission and mortality data. This is the first study investigating the association of outcomes after AMI in diabetic patients with metformin pre-treatment. We observed an older cohort, higher rates of previous cardiovascular disease and worse outcomes compared to other studies of AMI in diabetic patients [
29,
30], indicating that ours is a high-risk cohort.
Among over 4000 patients identified, the majority were receiving metformin at the time of index AMI, which was associated with worse outcomes with respect to the composite endpoint compared to patients on alternative oral hypoglycaemic agents. This which was driven by cardiovascular mortality and was the case despite similar glycaemic control in the two treatment groups, albeit it with higher rates of insulin prescription in the metformin group. This association was not evident in patients who survived the first month post index AMI, suggesting an acute, non-lasting effect. Interestingly, these findings only applied to patients taking metformin at the time of AMI, whereas post-AMI metformin use was associated with similar or reduced risk (and attenuated the strength of association in the primary analysis), in keeping with previous reports [
31]. Taken together and acknowledging potential bias associated with observational studies (including a more severe diabetes phenotype as indicated by a higher use of insulin in metformin users), these findings challenge reports of an acute infarct-sparing role for metformin.
With respect to cardioprotection at the time of AMI, several preclinical studies have demonstrated acute infarct size reduction and improved cardiac function with metformin [
11‐
15]. However, a recently published pre-clinical study of post-conditioning with metformin in pigs found no difference in infarct size or LV function compared to vehicle [
32]. Human studies have used biomarkers as a surrogate of infarct size in the context of STEMI [
16,
17]. A study of 660 diabetic patients with STEMI showed a reduction of infarct size (according to serum biomarkers) in the metformin group, although the comparator group were treated with diet alone, which may have exaggerated the effect [
16]. A propensity score matched analysis of 493 diabetic patients with STEMI showed no association between metformin and infarct size or LV function, although no information on drug treatment of diabetes in the control group was provided [
17]. In an analogous, randomized trial of oral metformin, started after primary percutaneous coronary intervention for STEMI in patients
without diabetes, no benefit was seen on LV function, MACE, all-cause mortality, or new-onset diabetes [
33,
34].
Our data also applies to patients with non-ST-segment elevation AMI (NSTEMI). Despite worse outcomes than patients presenting with STEMI [
35,
36], there is no evidence regarding the use of metformin in this context. We report an association between metformin use at the time of index AMI, including NSTEMI, and worse outcomes. This was unexpected and justifies further investigation.
We were unable to investigate the reasons for the association with worse outcomes in patients taking metformin at the time of index AMI. Traditionally, metformin is stopped on admission in these patients, due to concerns over lactic acidosis. However, there is a paucity of evidence for this and guidelines from the European Society of Cardiology (ESC) no longer recommend its routine cessation [
37‐
40]. Our findings may also relate to the metformin group being a sicker cohort with worse diabetic phenotypes as indicated by a higher use of insulin in metformin users. In critically ill patients there is a risk of hypoglycaemia-related morbidity associated with intensive glucose control with intravenous insulin [
41,
42], although we did not have data on acute glucose control in our study. In pre-clinical studies, increased myocardial rupture after AMI has been observed with metformin, which has been attributed to increased AMPK-MTOR/PGC-1α-mediated cardiomyocyte autophagy, but we were unable to assess this [
43].
Metformin use post-AMI
Despite these findings, metformin treatment has been shown to be advantageous in several pre-clinical and clinical studies of various cardiovascular diseases [
44‐
47]. Beneficial effects on mortality have been reported in patients started on metformin
after AMI, independent of its hypoglycaemic actions [
31]. This is typically attributed to the prevention of adverse ventricular remodelling [
48,
49]. However, these potential effects remain controversial and a recent meta-analysis of randomised trials indicated a non-statistically significant reduction of risk for most outcomes in metformin users, compared to non-users [
10]. In the present study, metformin use post-AMI was associated with a lower hazard ratio of MACE, which may support its use in patients at increased risk of cardiovascular disease.
Clinical relevance and further work
The ESC advocate the use of metformin, despite limited evidence, because of potential safety and economic benefits [
50]. The present study is consistent with its use in patients with T2DM but the association with worse outcomes among patients on metformin at the time of their AMI suggests that further investigation in well-designed randomised controlled trials is indicated, especially in view of the evidence and availability of alternatives. Although de novo randomised controlled trials of metformin are unlikely, the present study supports recent assertions that alternative approaches may comprise the inclusion of metformin in factorial trials and full publication of cardiovascular outcome data from previous trials of metformin [
10].
Strengths and limitations
The strengths of this study include, first, the use of three linked electronic data sources to maximise the ascertainment of outcomes. In addition, medication status and baseline characteristics were recorded prospectively, prior to AMI, limiting the possibility of recall bias. Second, the longitudinal study design and the analysis of metformin as a time-varying covariate that consider periods of use and non-use during follow-up. Third, we included patients on alternative hypoglycemics as the control group. This contrasts with similar studies that use a non-diabetic or untreated diabetic patient control arm and risk confounding due to difference in baseline characteristics. The results from the propensity score analysis were consistent, which increases confidence in our findings.
This study has the limitations of observational data, including potential bias because of unmeasured confounding factors (e.g. reperfusion status and indication bias). Therefore, we can only report associations and not causal relationships, and any results must be interpreted with caution, especially in view of clinical experience and economic indications for metformin use. Furthermore, although we accounted for HbA1c and prior insulin use, we were unable to adjust for other indicators of quality of diabetes management, including microvascular and other macrovascular complications, as these data were unavailable. However, the baseline characteristics of patients in our cohort were similar to each other and to those reported elsewhere [
16]. Further strengths and limitations are addressed in Additional file
1: Additional discussion.