Abstract
Objective: Metformin, commonly prescribed in diabetic patients, can cause lactic acidosis. Although generally rare, this side effect remains a source of concern in procedures requiring contrast media, due to the risk of contrast-induced nephropathy. Temporarily withdrawing metformin during the peri-procedural period is often practiced, but clinical decisions are difficult in emergency situations, such as acute coronary syndromes. In this systematic review with meta-analysis, we aimed to further investigate the safety of percutaneous coronary interventions in patients on concurrent metformin therapy.
Design, Setting and Participants: We analyzed studies in patients undergoing (elective or emergency) percutaneous coronary interventions with or without concurrent metformin administration, reporting on the incidence of metformin-associated lactic acidosis and peri-procedural renal function.
Methods: PubMed, ClinicalTrials.gov, Cochrane Library, and Scopus were systematically searched without language restrictions throughout August 2022. Randomized clinical trials and observational studies were assessed with the Revised Cochrane Collaboration Risk of Bias tool and the Newcastle-Ottawa quality scale, respectively. Data synthesis addressed the mean drop in estimated glomerular filtration rate (eGFR) and the incidence of contrast-induced nephropathy, in addition to lactic acidosis.
Results: Nine studies were included, totaling 2235 patients (1076 continuing metformin during the peri-procedural period), mostly with eGFR above 30 mL/min/1.73m2. No cases of lactic acidosis were reported. The mean post-procedural drop in eGFR was 6.81mL/min/1.73m2 (95% confidence interval [CI]: 3.41 to 10.21) in the presence of metformin and 5.34 mL/min/1.73m2 (95% CI: 2.98 to 7.70) in its absence. The incidence of contrast-induced nephropathy was not affected by concurrent metformin, as shown by a (between-groups) standardized mean difference of 0.0007 (95% CI: −0.1007 to 0.1022).
Conclusion: Concurrent metformin during percutaneous coronary interventions in patients with relatively preserved renal function is safe, without added risk of lactic acidosis or contrast-induced nephropathy. Thus, emergency revascularization in the context of acute coronary syndromes should not be deferred. More data from clinical trials in patients with severe renal disease are needed.
Percutaneous coronary interventions (PCI) have emerged as the standard of care in coronary artery disease. In the setting of acute coronary syndromes, primary PCI salvages myocardial tissue and improves outcome in the vast majority of patients.1,2 Despite the established benefit of primary PCI, the use of iodinated contrast media (CM), excreted solely by glomerular filtration, can cause acute kidney injury.3 The continuous refinement of CM in terms of ionicity, hydrophilicity, and osmolarity have minimized side-effects, but renal complications remain a concern, especially in patients with co-morbidities.4
Contrast-induced nephropathy (CIN), defined as significant deterioration of renal function in the absence of other causes, is mediated by various mechanisms, such as medullary ischemia, reactive oxygen species formation, or direct tubular cell toxicity.3-5 The incidence of CIN after coronary procedures is estimated at 2% in patients with normal renal function, but escalates up to 40% in patients with severe renal impairment.3-5 Its clinical manifestations occur invariably within 48 hours post-procedure, establishing CIN as a common cause of iatrogenic acute renal injury. Due to the high short- and long-term morbidity and mortality associated with CIN, substantial research efforts have been devoted to the prevention of this complication post-PCI.5
Diabetes mellitus is a well-known risk factor for coronary artery disease, with its prevalence constantly rising worldwide. In patients presenting with acute coronary syndromes, the incidence of diabetes was reported at 22.8% in a large cohort pooled from ten European registries.6 Most such patients are treated with metformin, which remains the preferred first-line therapy in type 2 diabetes.7 Alone or combined with other antidiabetic agents, metformin is effective and well tolerated, offering survival benefit in certain subgroups of patients.8 Moreover, a recent study showed ameliorated coronary endothelial dysfunction and lower rate of adverse cardiovascular events after chronic metformin administration in pre-diabetic patients,9 advocating for the extension of its clinical indications.
Despite the established benefits of metformin, this agent can cause lactic acidosis, often termed metformin-associated lactic acidosis (MALA), which is a rare but life-threatening condition, characterized by acidosis and elevated arterial lactate levels.10 In cases of MALA, lactate accumulation results from increased lactate production, coupled with reduced clearance.11 As metformin is excreted primarily through the kidneys, the incidence of MALA is higher in patients with renal impairment, raising concerns regarding metformin accumulation secondary to CIN. Despite the low risk for MALA, clinical dilemmas are common prior to procedures involving CM, due to the widespread use of metformin. This applies particularly to acute coronary syndromes, where the timeframe for clinical benefit via revascularization is short. The consequences of deferred primary PCI are important, as extensive myocardial necrosis increases complication rates, such as heart failure and arrhythmogenesis.
Addressing the risk of MALA, several bodies have issued recommendations, advising temporarily discontinuing metformin prior to interventions involving CM. Both the U.S. Food and Drug Administration and the consensus statement of Korean Diabetes Association and Korean Society of Nephrology suggest withholding metformin in patients who will receive intra-arterial iodinated CM regardless of baseline renal function.12,13 Similarly, the American College of Radiology recommend temporarily discontinuing metformin in patients undergoing intra-arterial contrast procedures.14 This has caused considerable controversy, with many investigators challenging this approach, based on the absence of solid data, especially in patients without co-morbidities.15-17 Therefore, the European Society of Urogenital Radiology recommend no need to discontinue metformin in patients with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 and no sign of acute kidney injucry, receiving intra-arterial CM with second pass renal exposure.18 However, previous analyses have included studies examining both intravenous and intra-arterial administration, although the risk of CIN in the latter appears higher.19 Based on the continuing uncertainty, we aimed at contributing to the ongoing debate by conducting a systematic review and meta-analysis on the safety of peri-procedural metformin administration in patients undergoing PCI. Our study, evaluating the impact of concurrent CM and metformin administration on renal function and the incidence of MALA, provides further data on the management of diabetic patients in emergency clinical situations.
Methods
We conducted a systematic literature search for published studies in PubMed, ClinicalTrials.gov, Cochrane Library and Scopus, available throughout August 2022. The search terms included “metformin”, “coronary angiography”, “angioplasty, transluminal, percutaneous coronary”, “acute coronary syndrome”, “cardiac catheterization” “acute kidney injury” and “contrast-induced nephropathy” (Supplementary File 1, available online). After examining the full text of pertinent studies, their references were manually checked for additional suitable articles. The methodology adhered to the guides summarized in PRISMA,20 and the study was registered in PROSPERO (CRD42021243302) with no deviations from the initial protocol. The data analysis and the report of the results also conforms to these guides, as seen in the PRISMA 2020 checklists (Supplementary Files 2 and 3, available online).
Eligibility Criteria
Eligible papers consisted of randomized clinical trials and observational studies without language restrictions, conducted in patients undergoing elective or emergency PCI for acute coronary syndromes, irrespective of the diagnosis of diabetes. There was no restriction regarding the date of publication. The incidence of MALA as well as CIN and eGFR (derived from creatinine clearance by means of the Cockcroft-Gault formula) were set as primary endpoints in patients with or without concurrent metformin administration during the peri-procedural period. In the continuing metformin cohorts, the respective control group consisted of patients undergoing PCI after withholding metformin or of drug-naïve patients.
Study Selection and Data Extraction
All authors independently examined each record. After screening the titles and abstracts, the full texts of potentially suitable articles were reviewed for eligibility. Randomized clinical trials and observational studies were assessed using the Revised Cochrane Collaboration Risk of Bias tool and the Newcastle-Ottawa Quality Scale, respectively. Original articles meeting the eligibility criteria were finally included in the analysis, and a PRISMA flow diagram was constructed. After creating a standardized data extraction form, the following information was obtained, in addition to study outcomes: title and study design, first author name, publication year, country of origin, sample size, and patient characteristics. We also recorded the type and volume of CM, PCI details (emergency versus elective), as well as the duration of metformin withholding period, or its dosage if continued. Data extraction was performed independently by all three authors, with inconsistencies resolved after discussion.
Definitions
In all included studies, CIN was defined as 25%–50% or 0.3–0.5 mg/dL (26.5–44.2 μmol/L) increase in serum creatinine levels within 48 hours following CM administration, according to widely accepted guides.5 The diagnosis of MALA was based on arterial blood pH<7.35 and elevated arterial lactate levels (>5.0 mmol/L), accompanied by metformin accumulation in the plasma (to concentrations >5 mg/L), as previously specified.10
Meta-Analysis
Meta-analysis was aided by the Jamovi software,21 with the mean difference in eGFR set as the outcome measure. The incidence of CIN (as a dichotomous outcome) in procedures with or without concurrent metformin was compared by calculating the standardized mean difference (with corresponding 95% confidence intervals [CI]) using the DerSimonian-Laird procedure,22 with values above 0.1 indicative of significant difference.23 After fitting a random-effects model to the data, heterogeneity was quantified, using the restricted maximum-likelihood estimator, the Q-test and the I2 statistic. Studentized residuals were used to examine outliers in the context of the model if they had a value higher than the 100[0.95/2(number of studies)]th percentile of a standard normal distribution. Studies with a Cook’s distance larger than the median plus 6 times the inter-quartile range were considered influential. The rank correlation test was used for the assessment of funnel plot asymmetry, using the standard error of the observed outcomes as predictor.
Results
Study Selection
After removal of duplicates, we identified 1,210 potentially suitable articles, the title and abstract of which were screened. At this stage, 482 reviews, systematic reviews, meta-analyses, editorials, letters, book chapters, or conference papers were excluded. The full text of the remaining 728 randomized clinical trials or observational studies were thoroughly assessed. Of these, 719 studies were further excluded either because the participants did not undergo coronary angiography, or because data on concurrent drug regimen, renal function, or MALA were absent (Figure 1). The remaining nine studies24-32 (one31 accessed through ClinicalTrials.gov) were included in the analysis.
Schematic diagram of how the papers were sought and selected.
Study Characteristics
A total of nine studies with a population of 2,235 patients were included in the analysis; eight24-31 were conducted in diabetic patients and one32 in non-diabetic patients. Of the total cohort, 1076 patients underwent PCI while treated with metformin during peri-procedural period, whereas metformin was absent in the remaining 1159 patients. There were five randomized clinical trials,26,27,30-32 (one32 in non-diabetic patients), two retrospective,28,29 and two prospective24,25 cross-sectional cohort studies, conducted in Europe, Asia, Canada, and the United States between the years 2010 and 2020. Seven studies24,26,27,29-32 enrolled patients without severe renal impairment, whereas no such entry criteria were set in the remaining two studies.25,28 All patients received low- or iso-osmolar CM, either ionic or non-ionic. Emergency only procedures were examined in four studies,25,28,29,32 elective only in three,26,27,31 and both types in two.24,30 The assessment of the included studies is provided in Supplementary Files 4-11 (available online), and their characteristics are summarized in Table 1.
Characteristics of the included studies
Main Findings
Data on the incidence of CIN in procedures with or without concurrent metformin are available from six studies.25,26,28-30,32 Heterogeneity measures by means of Cochrane Q-test revealed a value of 5.78 (P=0.32). The standardized mean difference was 0.0007 (or 0.07%, with 95% CI from −0.1007 to 0.1022), indicating comparable incidence of CIN in the two groups (Figure 2). Data derived from 552 diabetic patients in two studies26,29 indicated CM volume as an independent predictor of CIN. Initiation of aldosterone antagonists during hospitalization,32 impaired baseline renal function,29,32 age,25,32 left ventricular dysfunction,25,26 and N-terminal pro-B-type natriuretic peptide levels32 were also associated with higher risk of CIN.
Contrast-induced nephropathy. The incidence of contrast-induced nephropathy was not affected by continuing metformin during the peri-procedural period.
Meta-Analysis
Data on eGFR were collected from seven studies,24-29,32 none of which could be held as an outlier in the context of this model, based on studentized residuals lower than ±2.69. Likewise, no study could be considered overly influential, according to the Cook’s distances. The mean drop in eGFR in reference to baseline values in the presence or absence of metformin is depicted in Figure 3.
Effects of baseline renal function. Post-procedural drop in estimated glomerular filtration (eGFR) in each study, depicted in relation to baseline values.
Renal Function after PCI with Concomitant Metformin Administration
All studies showed a decrease in eGFR post-PCI, ranging from 1.8 to 12.2 ml/min/1.73 m2 (Figure 4). Based on the random-effects model, the estimated mean drop was 6.81 ml/min/1.73 m2 (95% CI:3.41-10.21), which differed from zero (z=3.92, P<0.0001). According to Q-test, the true outcomes appear heterogeneous (Q6=159.2, P<0.0001, tau2=18.13, I2=93.5%), but the rank correlation test indicated no funnel plot asymmetry. Based on these considerations, the model elicited a 95% prediction interval of −2.19 to 15.82 ml/min/1.73m2 for the true drop in the eGFR.
Post-procedural change in estimated glomerular filtration rate: metformin (+). Based on the random-effects (RE) model, the estimated mean drop in estimated glomerular filtration rate was 6.81 ml/min/1.73 m2 in patients on metformin during the peri-procedural period. The weight, effect size (ES) and 95% confidence intervals (CI) of each study are shown on the right.
Renal Function after PCI in the Absence of Metformin
After omitting one study24 (due to the absence of control group), a decrease in eGFR post-PCI was found, ranging from 1.1 to 8.0 ml/min/1.73 m2 (Figure 5). Based on the random-effects model, the estimated mean drop was 5.34 ml/min/1.73 m2 (95% CI:2.98-7.70), which differed from zero (z=4.44, P<0.0001). As the true outcomes appeared heterogeneous (Q5=77.3, P<0.0001, tau2=7.08, I2=92.4%), the model elicited a 95% prediction interval of −0.37 to 11.06 ml/min/1.73 m2 for the true drop in the eGFR.
Post-procedural change in estimated glomerular filtration rate: metformin (−). Based on the random-effects (RE) model, the estimated mean drop in estimated glomerular filtration rate was 5.34 ml/min/1.73 m2 in the absence of metformin during the peri-procedural period. The weight, effect size (ES) and 95% confidence intervals (CI) of each study are shown on the right.
Discussion
We analyzed nine studies, examining the incidence of MALA and renal complications post-PCI with or without concurrent metformin therapy. Although these studies included mostly patients without severe baseline renal impairment, data on patients with more advanced renal disease were derived from two studies.25,28 Our analysis provides information on (a) metformin concentrations post-PCI, (b) the incidence of CIN and MALA, and (c) eGFR decrease post-PCI in patients with renal impairment of varying severity.
Metformin Concentrations and Lactic Acidosis Post-PCI
Information on metformin plasma concentrations after CM administration in diabetic patients originates from one study.24 The peak concentration was observed approximately 4 hours after administration, displaying a similar trend with reference values in healthy volunteers. More importantly, drug concentrations showed no metformin accumulation post-procedure. Although our meta-analysis (involving 2,235 patients mainly without severe renal impairment) may be underpowered to detect a significant difference in incidence of CIN and consequently of MALA, this finding may explain the absence of MALA in all analyzed studies,24-32 examining a pooled cohort of 1076 patients undergoing PCI on concurrent metformin treatment. On the other hand, a word of caution arises from the study by Shavadia,30 in which metformin continuation resulted in higher lactate levels, as compared to a 48-hour discontinuation.
Changes in eGFR Post-PCI
In patients with baseline eGFR above 30 mL/min/1.73 m2, eGFR decreased post-PCI by approximately 10%, although a wide variation was present, apparently unrelated to baseline values. The post-procedural decrease in eGFR was not only unaffected by concurrent metformin therapy, but, interestingly, a protective potential of metformin on renal function cannot be excluded, based on the prediction intervals.
Nephroprotective and Pleiotropic Effects of Metformin
The notion of metformin associated with nephroprotective effects is supported by data derived from two studies.25,26 In the study by Oktay et al,26 eGFR decreased only marginally in patients continuing metformin during the peri-procedural period, as opposed to a more prominent decrease in its absence. Likewise, in the study by Zeller et al,25 the rate of CIN post-PCI tended to be lower in patients on metformin, as compared to other oral antidiabetic agents. However, this trend was lost when only the subset of patients with baseline eGFR below 60mL/min/1.73m2 was examined, suggesting the possible nephroprotective effects of metformin were not sustained in this group. Based on the previously described modulatory effects of metformin on inflammatory and oxidative responses,33,34 our findings call for further research on the pleiotropic actions of metformin on the kidney.
Pleiotropic activity and favorable properties of metformin may also provide a cardioprotective advantage in patients with acute coronary syndromes, since animal models and clinical studies demonstrated that acute coronary syndromes are accompanied by complex inflammatory systematic responses, which incorporate a number of different mediators and determine many clinical outcomes.35 Metformin administration reduced infarct size and ventricular remodeling, and improved ventricular function and hypoxia/reoxygenation injury in a series of preclinical studies.36,37 Furthermore, metformin continuation in acute coronary syndrome population may modify systematic inflammatory response, as well as inflammatory-mediated cardiorenal crosstalk, affecting mortality and magnitude of renal function deterioration.38,39
Strengths and Limitations
Our study focused on the safety of concurrent metformin treatment in patients undergoing PCI, a topic of high clinical significance, given the salutary effects of PCI in the setting of acute coronary syndromes. Moreover, we thoroughly analyzed the few available data in diabetic patients with severe renal impairment who are at the highest risk for CIN post-PCI. Despite these strengths, two limitations should be acknowledged. First, the pooled number of patients is relatively small. Given the wide variation of the well-established confounding factors of CM volume, a larger cohort would have permitted more accurate conclusions. Second, there were only three fully published randomized clinical trials in diabetic patients. More information is awaited from an ongoing study40 in patients with eGFR >45 mL/min/1.73 m2.
Conclusions
Our analysis demonstrates that concurrent metformin treatment during PCI is safe. The risk of MALA is extremely low, whereas metformin does not appear to increase the risk of CIN in patients with eGFR above 30 mL/min/1.73 m2. Thus, our data argue against deferral of emergency PCI in such patients. Further larger-scale clinical trials in diabetic patients with severe renal impairment present on hospital admission undergoing emergency PCI are eagerly awaited. Our analysis provides an important safety background for their design.
Footnotes
Disclosure: The authors have not reported financial support or personal conflicts of interest related to this work.
- Received April 18, 2022.
- Revision received October 6, 2022.
- Accepted October 6, 2022.
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