Activating the Flozin Shield: Cardioprotective Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Kidney Transplant Recipients With Diabetes Mellitus

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Diabetic kidney disease, an all-encompassing term that includes both micro and macrovascular complications, is the leading cause of end-stage kidney disease worldwide. Posttransplant diabetes mellitus, a common complication after solid organ transplantation, is associated with graft loss, cardiovascular events, and all-cause mortality.¹ Two landmark trials in the 1990s, the United States National Institutes of Health-sponsored Diabetes Control and Complications Trial and the United Kingdom Medical Research Council-sponsored United Kingdom Prospective Diabetes Study, established the benefits of tight glucose control on the microvascular complications in individuals with type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM), respectively. Paradoxically, intensive therapy to target normal glycated hemoglobin levels, compared with standard treatment, increased all-cause mortality and did not significantly reduce major adverse cardiovascular events (MACE).² Worried about the increased cardiovascular mortality of antidiabetic drugs, the United States Food and Drug Administration issued guidance in 2008 that required the pharmaceutical industry to show cardiovascular safety in new drug applications for treating T2DM (the new 2020 guidance recommended a broader approach for safety evaluations beyond cardiovascular risk).

Glucose in tissue is transported by 2 families of transporters—the sodium-glucose cotransporters (SGLT/SLC5) and facilitated glucose transporters (GLUT/SLC2). The distribution of SGLT2 is mainly in the kidney proximal tubular cells. In 1835, 2 Belgian physicians, de Koninck and Stas, isolated phlorizin (Petersen, a French chemist, is also credited for this) from the root bark of the apple tree and used it to treat fever; its glucosuric effect was discovered in 1886 by von Mering, a German physician, after oral and subcutaneous administration in dogs. He also observed decreasing glycemia with increasing glucosuria. Phlorizin, a nonselective SGLT inhibitor (SGLTi), was, however, poorly tolerated as an oral drug for diabetes because of its gastrointestinal side effects. An O-glucoside analog of phlorizin—T-1095—was developed by Japanese investigators in 1999 as a selective SGLT2i.³ Subsequently, in 2008, scientists at Bristol-Myers Squibb and AstraZeneca developed a more stable C-glucoside analog, dapagliflozin, which, after an initial US Food and Drug Administration non-approval in 2012 due to safety concerns, received approval in 2014 (earlier approved by the European Medicines Agency in 2012) as an oral drug to improve glycemic control in adults with T2DM.

The 2015 EMPA-REG OUTCOME trial was a game changer; 7028 patients with T2DM with a body mass index of ≤45 and an estimated glomerular filtration rate of at least 30 ml/min and established cardiovascular disease (history of stroke or myocardial infarction, or evidence of coronary artery or occlusive peripheral artery disease), and a glycated hemoglobin level of at least 7% were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in the pooled empagliflozin versus the placebo group. The hazard ratio for the primary outcome in the pooled empagliflozin group was 0.86 (95% confidence interval 0.74–0.99), and for all-cause mortality was 0.68 (0.57–0.82). This 32% reduction in all-cause mortality translated to treating 39 patients for 3 years to prevent 1 death.⁴ Soon, it became clear that SGLT2i were not only glucosuric but also prolonged life in individuals with reduced left ventricular ejection fraction regardless of the presence or absence of T2DM.

The benefits of SGLT2i in native kidney disease are unequivocal. Kidney Disease Improving Global Outcomes 2024 provides a 1A recommendation (high certainty of evidence) for treating (i) patients with T2DM, chronic kidney disease, and an eGFR ≥20 ml/min, (ii) adults with chronic kidney disease with an eGFR ≥20 ml/min and urine albumin creatinine ratio ≥200 mg/g, or (iii) adults with chronic kidney disease and heart failure irrespective of the level of albuminuria with an SGLT2i. For adults with an eGFR between 20 and 45 and urine albumin creatinine ratio <200 mg/g, the recommendation level for SGLT2i is 2B (moderate certainty of evidence).⁵

However, data on the safety and efficacy of SGLT2i in kidney transplant recipients (KTRs) are sparse. Small observational studies and one small, randomized study have shown that SGLT2i improves glycemic control, lowers body weight, and lowers blood pressure in KTRs.⁶ In such a context, the study published in this issue of the Journal by Lim et al.,⁷ investigating the cardioprotective effect of SGLT2i in diabetic KTRs is critical. An earlier paper by the authors showed that SGLT2i improved a composite of all-cause mortality, death-censored graft failure, or serum creatinine doubling in KTRs. The present study included 750 KTRs with diabetes (median age 55 years, 70% male, 16% posttransplant diabetes mellitus) at 6 hospitals in Korea. Individuals with heart failure, acute coronary syndrome, or stroke, and who had received coronary artery intervention within 3 months before the transplant were excluded. The primary outcome was MACE, which included myocardial infarction, stroke, hospitalization for heart failure, or death from cardiovascular causes. Of the 750 KTRs with diabetes, 129 were, and 621 were not on SGLT2i. The median follow-up was 56.3 months (interquartile range, 44.1–70.3) post transplantation. The incidence of MACE was 4.7% in SGLT2i users and 12.6% in SGLT2i nonusers. After adjusting for multiple variables, the hazard ratio for MACE in the SGLT2i group was 0.37 (95% confidence interval 0.16–0.87).

Of the 129 patients who received SGLT2i, 127 were propensity score-matched with SGLT2i nonusers. Propensity score is a statistical technique for replicating a randomized controlled trial using observational data. Here, a score calculated for a subject in an observational study using the observed baseline characteristics describes the subject’s probability of belonging to the treatment group. The score can be used mainly in 3 ways—covariate adjustment, stratification, and matching. There are several matching algorithms; the nearest-neighbor (greedy) matching is widely applied. Typically, a 1:1 propensity score matching between the intervention and control group is used. However, when the control group includes more subjects, other ratios (1:2, 1:3, etc.) are used to increase the statistical power. The authors used a nearest neighbor 1:1, 1:2, and 1:3 matching. The incidence of MACE in the 1:1 matched population was 3.9% among SGLT2i users and 11.8% among SGLT2i nonusers; the hazard ratio was 0.30 (95% confidence interval 0.10–0.88). Notably, the incidence of bacterial urinary tract infections (UTI) did not differ between the groups, but fungal UTI was higher among SGLTi users.

The observational design, which has unique challenges, is a significant limitation of this study. The SGLT2i was started at 13.4 months (median, interquartile range 2.4–30.1) post transplantation. Because the authors treated SGLT2i use as a baseline and not a time-dependent variable, this would have led to the immortal time (time-dependent) bias, likely underestimating the true hazard ratio.⁸ Also, of the 129 patients taking SGLT2i, 18 (14%) stopped the drug during follow up. Nevertheless, the study by Lim et al.⁷ is a vital addition to the growing body of literature on the benefits of SGLTi in kidney recipients. In addition, data on the effects of SGLT2i on the immune system are emerging, which could be favorable for KTRs.⁹ These drugs suppress NLRP3 inflammasome, attenuate the release of proinflammatory cytokines from macrophages via downregulating NF-κB, MAP kinase, and Jak/Stat pathways, affect T cell effector function and differentiation via metabolic reprogramming, and increase regulatory T cell subsets, among others. Hence, it is time for transplant providers to embrace the pleiotropic benefits of SGLT2i and activate the flozin shield for their patients!

Disclosure

All the authors declared no competing interests.