Patients with diabetes who were taking metformin prior to major surgery had a lower mortality rate 90 days after the procedure compared to patients who had not been taking metformin, a retrospective, propensity score-matched cohort study found.
The metformin-exposed group was also less likely to require hospital readmission at 30 and 90 days postoperatively and they had better long-term survival rates compared to patients who had not been treated with metformin preoperatively, the same study showed.
“Previous studies demonstrated that treatment with metformin was associated with a decrease in all-cause mortality,” Katherine Reitz, MD, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania and colleagues wrote in JAMA Surgery.
“This study extends these findings by demonstrating that preoperative metformin prescriptions were associated with a reduction in postoperative mortality and readmission, a surrogate for postoperative complications, and with long-term mortality,” they stated.
The study involved a total of 10,088 adults with type 2 diabetes who underwent a major surgical intervention between January 2010 and January 2016 at 15 community and academic hospitals within a single health care system in Pennsylvania.
“We defined preoperative metformin exposure as 1 or more prescriptions for metformin in the 180 days before the surgical procedure and as inclusion of metformin on the active medication list during the most recent preoperative encounter before the surgical procedure,” investigators explain.
The primary outcome was mortality at 90 days following surgery while secondary outcomes were mortality at 30 days postoperatively, 30 and 90-day post-discharge readmission rates and mortality at 5 years.
A total of 5460 patients or 54% of the total cohort were successfully propensity matched.
“Most of the surgical interventions were general… or orthopedic… of which… 24% used a minimally invasive approach,” Reitz and colleagues noted.
Each treatment group was followed for a mean of over 4.5 years (95% CI, 4.6-4.9 years) and 4.6 years (95% CI, 4.5-4.7 years).
Mortality at day 90, the primary end point of the study, was 3% among patients who had been exposed to metformin preoperatively compared with 5% of those who had not been exposed to preoperative metformin, as the authors reported.
At 5 years, 13% of those exposed to metformin preoperatively had died compared 17% of those who had not been prescribed metformin prior to surgery.
“The association between metformin and the reduced risk of 90-day mortality was statistically significant for those who underwent a general surgical intervention [matched ARR (absolute risk reduction) 2.02; 95% CI, −0.18-3.85] and was similar across other surgical specialties, excluding neurosurgery,” investigators pointed out.
The association between preoperative metformin and reduced 90-day mortality also held true for both emergency surgery (matched ARR, 0.38; 95% CI, −2.25-9.81) and elective surgery (matched ARR, 1.00; 95% CI, 0.02-1.93).
Hospital Readmissions
At 30- and 90-days post-discharge, hospital readmission rates were also lower among those who had been exposed to metformin preoperatively compared to those who had not.
At 30 days post-discharge, 11% of the metformin-exposed required hospital readmission as did 20% of the same group at 90-days post-charge.
These rates compared to 13% at 30 days post-discharge among of the non-exposed group and 23% by day 90, researchers added.
Prior to the surgical procedure, patients who had received a metformin prescription also had statistically significantly lower preoperative markers of inflammation as reflected by a mean neutrophil to leukocyte ratio of 4.5 (95% CI, 4.3-4.6) compared to those who had not received a prescription at a mean of 5.0 (95% CI, 4.8-5.3; P<0.001). The neutrophil to leukocyte ratio is a marker of systemic inflammation.
As the authors suggested, the pleiotropic advantages of metformin in the present cohort may positively modulate the inflammatory response to major surgery to improve outcomes, although this remains an unproven hypothesis.
Limitations to the study include an inability to quantify the surgical stress experienced by patients postoperatively.
“All variables were extracted retrospectively from the EHR (electronic health records) of a multicenter, single health care system,” Reitz and colleagues pointed out: as a consequence, any patient who received a prescription outside of the system was at increased risk for misclassification and underreported information.
Moreover, the preoperative duration and dose of metformin were unknown.
“Without this information, neither a temporal nor dose response relationship can support the causal inference,” the authors cautioned.
Commenting on the findings, Elizabeth George, MD, and Sherry Wren, MD, both from Stanford University School of Medicine in Palo Alto, California suggested that the study shows how variables such as metformin use prior to surgery can affect surgical outcomes.
However, as they cautioned, statins have also been associated with improved postoperative outcomes, but statins were not considered as a unique variable in this particular study.
This despite the fact that over 60% of the matched and unmatched subcohorts had been prescribed a statin.
“Since both statins and metformin are anti-inflammatory and immunomodulatory agents, it is important that they are adjusted for in the model,” George and Wren pointed out.
Thus, the editorialists recommended that any future studies on the evaluation of metformin and its effect on surgical outcomes need to either exclude patients taking statins or at the least investigate possible interactions between the 2 agents.
“We would be interested in seeing a subanalysis of this data set that excluded patients who were prescribed statins,” George and Wren observed.
“These data would further solidify the role of metformin as a possible modifiable perioperative factor,” the editorialists concluded.
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Patients with diabetes who were taking metformin prior to having major surgery had a lower mortality rate at 90 days and at 5 years than patients who were not taking metformin preoperatively.
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Hospital readmission rates, a surrogate for surgical complications, were also lower among patients exposed to preoperative metformin than among those who were not exposed.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded internally by the UPMC.
Reitz had no conflicts of interest to declare but other investigators did which are listed in the publication.
Neither George nor Wren had any conflicts of interest to declare.
Cat ID: 12
Topic ID: 76,12,730,12,669,918,159
