Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis

概要

1. Introduction
Type 2 diabetes mellitus (DM) is a major public health problem with a high prevalence, and the number of DM patients is expected to increase. It is known that DM is associated with an increased risk of cardiovascular disease and mortality. Moreover, type 2 DM is the leading cause of chronic kidney disease (CKD), accounting for roughly 36% of adult CKD in the United States. CKD with DM can progress to end-stage renal disease, which confers a poor prognosis. (Yandrapalli et al. 2017) Therefore, the prevention of CKD progression and cardiovascular events is essential for the management of patients with type 2 DM and CKD.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are new classes of glucose-lowering agents. Besides the glucose-lowering effect, SGLT2 inhibitors and GLP-1 RAs improve cardiovascular events. (Zelniker et al. 2019) The American Diabetes Association (ADA) recommends SGLT-2 inhibitors or GLP-1 RAs in type 2 DM patients who have atherosclerotic cardiovascular disease or kidney disease. So far, no study has compared the effect of SGLT-2 inhibitors on renal and cardiovascular diseases with that of GLP-1 RAs in CKD patients, who are at a high risk of morbidity. We herein investigate the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients by network meta-analysis.

2. Methods
We performed a systematic search of PubMed, Medline, EMBASE, and the Cochrane Library from inception to November 20, 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We extracted a subgroup data of patients with CKD, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 . The primary efficacy outcome of this analysis was 3-point MACE (MACE-3), including cardiovascular death, myocardial infarction (MI), and stroke. The secondary outcome was a composite of renal outcomes, including ESRD, a decline in kidney function, and renal death. We performed a network meta-analysis using R programming language. We compared SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.

3. Results
Thirteen studies (six studies were randomized control trials (RCTs) that compared SGLT-2 inhibitors with placebo; seven studies compared GLP-1 RAs with placebo) were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95 %CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). Next, we performed a sensitivity analysis of GLP-1 RAs subclass: GLP-1 analogues and exendin-4 analogies. The analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]). Lastly, we conducted a subgroup analysis based on eGFR: 30-44 ml/min/1.73m2 and 45-59 ml/min/1.73m2 . In a subgroup of eGFR: 30-44 ml/min/1.73m2 patients, SGLT-2 inhibitors reduced MACE-3 and renal outcomes significantly (RR 0.73 [0.54-0.97] and 0.75 [0.62-0.91, respectively), but GLP-1 RAs did not (RR 1.02 [0.78-1.33] and 0.78 [0.46-1.32], respectively). For patients with eGFR 45-59 ml/min/1.73m2 , both SGLT-2 inhibitors and GLP-1 RAs had a similar tendency to reduce MACE-3 compared to placebo (RR 0.82 [0.66-1.01] and 0.85 [0.71-1.03], respectively). SGLT-2 inhibitors reduced renal outcomes (RR 0.61 [0.48-0.77), but GLP-1 RAs did not (RR 1.18 [0.76-1.84]).

4. Discussion
To the best of our knowledge, this is the first study that investigated the cardiovascular and renal risk of SGLT-2 inhibitors and GLP-1 RAs. Our study revealed that SGLT-2 inhibitors decrease the risk of cardiovascular and renal events in type 2 DM patients with CKD. On the other hand, GLP-1 RAs did not lead to significantly lower cardiovascular or renal endpoints, although they showed numerically better results. An indirect comparison of SGLT-2 inhibitors with GLP-1 RAs revealed that SGLT-2 inhibitors significantly decreased the risk of renal outcomes. Interestingly, a sensitivity analysis among GLP-1 RA subclasses revealed that GLP-1 analogs significantly reduced MACE-3 and renal events, while exendin-4 analogs did not. Possible mechanisms for the positive impact of SGLT-2 inhibitors include natriuretic effects, mitigation of low-grade inflammation, and reduced delivery of sodium to the macula densa, which leads to a reduction in intraglomerular pressure. (Imprialos et al. 2015) Our sensitivity analysis among GLP-1 RAs subclasses revealed a beneficial effect of GLP-1 analogs, while exendin-4 analogs were not. Differences between GLP-1 analogs and exendin-4 analogs include metabolization and elimination of the drug. (Gorriz et al. 2020) Further studies are warranted to explore the differences among GLP-1 RAs subclasses. Limitations of our meta-analysis include high heterogeneity, which persisted in most sensitivity and subgroup analyses, different definitions of renal outcomes across studies. To conclude, in patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogs showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogs did not.

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