Outcomes With Metformin Use in Kidney Transplant Recipients

The leading cause of chronic kidney disease (CKD) is diabetes. For patients with diabetes and CKD that has progressed to end-stage kidney disease (ESRD), the preferred treatment is kidney transplantation. According to data from survival analyses from the US Renal Data System, patients with diabetes who receive a kidney transplant have a 73% reduction in the risk of all-cause mortality compared with patients with diabetes on the transplant wait list. Further, kidney transplant recipients without diabetes are at risk of developing post-transplantation diabetes mellitus (DM).

Metformin is the most commonly prescribed oral antidiabetic agent worldwide and is considered a first-line agent in the pharmacologic management of type 2 DM. Due to concerns regarding an increased risk of lactic acidosis, metformin use has been avoided in patients with CKD with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m².

However, according to Soie Kwon, MD, MS, based on recent evidence of a low incidence of lactic acidosis as well as benefits that include improved survival rate and renoprotective effects, the  use of metformin has been increasingly recommended for patients with advanced CKD. A previous study also reported that metformin usage by patients with advanced CKD improved the risk of all-cause mortality and ESKD.

The researchers conducted a retrospective multicenter cohort study to test the hypothesis that the use of metformin would be beneficial in kidney transplant recipients in terms of all-cause mortality and renal outcomes, including death-censored graft failure (DCGF) and biopsy-proven acute rejection (BPAR). They also sought to assess whether there is an associated between metformin usage and risk of lactic acidosis in kidney transplant recipients. Results were reported in the American Journal of Kidney Diseases [2023;82(3):290-299].

The study cohort included 1995 kidney transplant recipients with diabetes from six tertiary referral centers in the Republic of Korea. Metformin usage was defined as the use of metformin for more than 90 days following kidney transplantation. Of the 1995 study participants, 1193 were metformin users; the remaining 802 did not use metformin. The primary study outcome was all-cause mortality and DCGF. Secondary outcomes were BPAR and lactic acidosis events.

In the overall cohort, 78.4% of patients (n=1565) were diagnosed with pretransplantation DM versus 21.6% (n=430) who were diagnosed with post-transplant DM. Patients in the pretransplant diabetes group tended to have fewer prescriptions for metformin than those in the post-transplant diabetes group (n=897, 57.3% vs n=296, 68.8%, respectively; P<.001).

In the pretransplant diabetes group, the primary cause of ESKD was DM (DM-ESKD, 83.4%, n=1305). Those patients tended to have fewer prescriptions for metformin compared with patients with ESKD from other causes. The proportion of metformin users in the DM-ESKD group was 56.6% (n=728/1305), and in the group with ESKD from other causes, the proportion of metformin users was 61.2% (n=159/260), P<.001.

Baseline characteristics differed between the metformin users and the non-metformin users, particularly with respect to renal function and glycemic control. Renal function was better among metformin users (higher eGFR in the third month after kidney transplantation; P<.001), greater proportion of living donors compared with non-metformin users (P<.001), and poorer glycemic control (higher hemoglobin A1C in the third month after transplantation, P<.001). Metformin users also had greater proportion of several oral antidiabetic agent prescriptions compared with non-metformin users. There were no differences between the two groups in insulin usage.

Mean study follow-up was 72.6 months. During follow-up, 94 of the 1995 patients died. The three leading causes of death were infection-related (44.7%, n=42/94), malignancy-related (20.2%, n=19/94), and cardiovascular/sudden death (13.8%, n=13/94). Results of Cox analyses revealed a significantly lower risk of all-cause mortality compared with non-metformin users (univariate analysis; adjusted hazard ratio [aHR], 0.39; 95% CI, 0.26-0.58; P<.001). In the landmark analysis, the risk of all-cause mortality was lower in metformin users compared with non-metformin users, although the difference was not statistically significant (model 3; aHR, 0.94; 95% CI, 0.32-2.76; P=.915).

During a mean follow-up of 64.7 months, 5.1% of patients (n=102/1995) experienced a graft failure. Metformin users had a lower risk of graft failure, even after accounting for the competing risk of all-cause mortality. Following adjustment for time-varying confounding, hemoglobin A1c, metformin usage, and mean daily dose, the risk of DCGF remined significantly lower in metformin users compared with non-metformin users (aHR, 0.47; 95% CI, 0.23-0.96; P=.038).

Patients who experienced the first BPAR prior to a post-transplant diagnosis of DM were excluded from the analysis of metformin usage and BPAR. During mean follow-up of 65.6 months, BPAR was diagnosed in 11.6% of patients (n=213/1830). Following adjustment for time-fixed covariates, there was an association between metformin use and lower risk of BPAR; the association did not reach statistical significance (aHR, 0.98; 95% CI, 0.62-1.54; P=.0924).

The occurrence of lactic acidosis was evaluated in 90.8% of the cohort (n=1801/1995). Seventy-seven lactic acidosis events were recorded in 66 of the 1801 patients (3.67%). There was no confirmed case of lactic acidosis associated with metformin use.

In subgroup analysis, there were associations between metformin use and reduced risk of all-cause mortality, and metformin use and a lower risk of DCGF for both patients with pretransplant DM and those with post-transplant DM. Use of metformin was associated with a lower risk of BPAR in the post-transplant DM group; it was less effective in the group with pretransplant DM. There was also a correlation between a higher dose of metformin and lower risks of DCGF and BPAR.

The researchers cited some limitations to the study, including the inability to obtain data on covariates (diabetes duration prior to transplantation and diuretic usage) and outcomes (major adverse cardiovascular events); limited data on newer antidiabetic drugs such as sodium-glucose cotransporter-2 (SGLT2) inhibitors; and limited generalizability to other populations.

In conclusion, the authors said, “Metformin usage may be beneficial for kidney transplant recipients, as evidenced by its association with a reduced risk of DCGF and the absence of metformin-associated lactic acidosis events. In the future, further well-designed randomized controlled trials with post-transplant DM defined according to American Diabetes Association criteria and that account for SGLT2 inhibitor use are needed to validate our findings.”

Takeaway Points

1. Researchers in the Republic of Korea conducted a retrospective cohort study to examine the clinical effects of metformin in kidney transplant recipients.
2. There was a significant association between metformin use and a lower risk of death-censored graft failure. There was no confirmed case of lactic acidosis associated with metformin use.
3. There was no significant association between metformin use and all-cause mortality or biopsy-proven acute rejection.

Source: American Journal of Kidney Diseases