Preoperative metformin may improve postoperative outcomes in T2D

Adults with type 2 diabetes (T2D) on preoperative metformin therapy could have better postoperative outcomes, a US-based retrospective cohort study showed.

“This study … demonstrate[ed] that preoperative metformin prescriptions were associated with a reduction in postoperative mortality and readmission, a surrogate for postoperative complications, and with long-term mortality,” said the researchers.

Electronic medical records of a single healthcare system in Pennsylvania, US, were used to identify 10,088 adults with T2D who underwent major surgery* between January 2010 and 2016. Of these, 5,460 were propensity score-matched 1:1 (mean age 67.7 years, 53 percent female, 89 percent Caucasian), with 2,730 individuals with and without preoperative metformin prescriptions, respectively.

Thirty-five percent of participants were treated with insulin and had adequate glucose control (mean HbA_1c 7.1 mmol/mol). Mean surgical duration was longer in patients with vs without preoperative metformin prescriptions (175 vs 169 minutes; p=0.02), though estimated mean intraoperative blood loss was comparable (122 vs 119 mL; p=0.67). Postoperative metformin prescriptions at 1 year were reported in 95 and 8 percent of those with and without preoperative prescriptions, respectively.

Ninety-day all-cause postoperative mortality was reduced among individuals with preoperative metformin prescriptions** (adjusted hazard ratio [adjHR], 0.72, 95 percent confidence interval [CI], 0.55–0.95; p=0.02), with a significant absolute risk reduction (ARR) of 1.28 percent. Five-year all-cause mortality was also reduced among those with preoperative metformin prescriptions (adjHR, 0.74, 95 percent CI, 0.65–0.85; p=0.001). [JAMA Surg 2020;doi:10.1001/jamasurg.2020.0416]

Preoperative metformin prescriptions were also tied to a reduced risk of hospital readmission at 30 and 90 days (ARR, 2.09 and 2.78, respectively; p=0.03 for both), with reduced subhazards of readmission at days 30 and 90 (sub-HR, 0.84; p=0.02 and sub-HR, 0.86; p=0.01, respectively), with death as a competing risk.

Inverse probability weighting analysis of the whole cohort (n=10,088) showed a 22 percent increase in 5-year survival with vs without metformin prescriptions.

As the emergence of new disease states in the immediate perioperative period is unlikely, these findings suggest “that metformin has ongoing physiological implications beyond its known association with chronic diseases, healthcare use, and glycaemic control,” said the researchers.

“[T]he advantages are likely not disease specific,” they continued, noting the lack of difference in metformin-associated outcomes across the different surgical specialities. “[T]he pleiotropic properties may modulate the stress response generated by a major surgical intervention or confer consistently good outcomes, regardless of the surgical procedure.”

Systemic preoperative inflammation, as measured by neutrophil:leukocyte ratio (NLR), was significantly lower in those with vs without metformin prescriptions (mean 4.5 vs 5.0; p<0.001).  “[L]ower preoperative inflammation can estimate superior perioperative morbidity and mortality,” said the researchers.

“This study demonstrates how variables besides coexisting medical diseases can affect surgical outcomes,” said Professor Sherry Wren and Dr Elizabeth George from the Stanford University School of Medicine, Stanford, California, US, in an editorial. [JAMA Surg 2020;doi:10.1001/jamasurg.2020.0417]

“Metformin now joins β-blockers, statins, and immunonutrition as preoperative agents associated with improved surgical outcomes. It may be only a matter of time before optimization of postoperative outcomes with perioperative medications and supplements becomes a standard,” they said.

Study limitations included potential residual confounding, varying surgical stress levels or preoperative metformin dosage or duration, lack of information on out-of-system prescriptions, and under-reporting of readmission.

Wren and George also noted the lack of adjustment for statins – anti-inflammatory and immunomodulatory agents – despite their use in more than 60 percent of the study population. They recommended that future studies on metformin outcomes consider the possible metformin-statin interaction or exclude patients on statins.