Effects of sodium‐glucose cotransporter type 2 inhibitors on cardiovascular, renal, and safety outcomes in patients with cardiovascular disease: a meta‐analysis of randomized controlled trials

Abstract

Background Controlled studies and observational studies have shown that sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for the survival of patients with heart failure (HF). However, it is unclear whether SGLT-2i can provide benefit in patients with other cardiovascular diseases. Here, we conducted a systematic review and meta-analysis to determine the outcomes of cardiovascular, renal, and safety outcomes of SGLT-2i administration in patients with cardiovascular diseases. Methods We searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and ClinicalTrials.gov databases for randomised controlled trials written in English from inception until November 1, 2020. Two reviewers independently identified randomised controlled trials comparing the effects of SGLT-2i in patients with cardiovascular disease with or without diabetes. Primary outcomes were cardiovascular outcomes and renal outcomes. Secondary outcomes were safety outcomes, including adverse endocrine outcomes and adverse infection outcomes. The effects of SGLT-2i were evaluated using RevMan5.3 software. The Cochrane risk of bias tool was used to assess study quality. Results We identified 10 randomised controlled trials (25,108 patients in the SGLT-2i group and 18,574 patients in the placebo group). Meta-analysis revealed that SGLT-2i treatment significantly reduced all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (HHF) in patients with cardiovascular disease (all-cause mortality relative risk [RR]: 0.86; 95% confidence interval [CI] 0.81–0.91; P < 0.00001; I2 = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79–0.92; P < 0.0001; I2 = 26%; HHF RR: 0.69; 95% CI 0.64–0.81; P < 0.00001; I2 = 0%). In patients with HF, mortality and HHF after SGLT-2i treatment for HF with reduced ejection fraction were significantly reduced, whereas HF with preserved ejection fraction did not differ compared with placebo treatment. Moreover, SGLT-2i induced a lower incidence of renal damage and myocardial infarction than the placebo group; however, the risk of infection, amputation, volume depletion, and diabetic ketoacidosis was higher. Conclusions SGLT-2i had significant clinical effects on cardiovascular outcomes and significantly influenced acute kidney injury. The effects of SGLT-2i on cardiovascular disease were independent of diabetic status. Sotagliflozin could have advantages over other SGLT-2i in lowering HHF.

Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence

“…Other studies specifically focused on populations with T2D and CKD or HFrEF [ 8 , 9 , 14 ]. They generally found that compared with placebo SGLT2i protect the kidney and reduce the incidence of hHF [ 2 – 4 , 6 , 8 – 10 , 12 – 14 , 28 , 29 ]. However, due to the relatively high baseline risk of the participants in these trials, external validity to the general T2D population has been questioned [ 30 ].…”

“…Such trends were observed in other CVOTs and other real-world evidence (RWE) [ 2 – 4 , 6 , 34 ]. Of note, in these reports SGLT2i reduce hHF episodes more overtly relative to ACM [ 6 , 28 ]. Here, however, in the low baseline kidney risk categories ACM incidence was consistently lower in SGLT2i initiators, while the risk for hHF was not stable, i.e., significant between group differences were observed only in the eGFR > 90 ml/min/1.73 m 2 category.…”

“…Our registry does not specify the cause of death, precluding us from testing the association between SGLT2i initiations and CV death, as a component of the classical major adverse cardiovascular event (MACE) composite outcome, amongst other possible causes of death. Relevantly, several SGLT2i randomized controlled trials (RCTs) and RWEs have found lower incidence of ACM, suggesting an effect that may extend beyond MACE (EMPA-REG OUTCOME, DAPA-CKD) [ 1 , 10 , 28 , 34 ]. Other outcomes (e.g., hHF) may be affected by variations between physicians’ reporting.…”

Cardiovascular and mortality benefits of sodium–glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus: CVD-Real Catalonia

“…However, the relative effectiveness of each product on the different outcomes remains to be elucidated, because study populations and designs are different. Recent attempts to indirectly address this issue through network meta-analyses led to differing conclusions regarding the differential effect of individual SGLT2i on outcomes such as HF and all-cause mortality [ 44 , 45 ]. Therefore, in the absence of prospective or retrospective head-to-head trials comparing individual SGLT2i, it cannot be ascertained to what extent the exposure to the individual SGLT2i in CVD-REAL Catalonia vs. other studies could have contributed to the observed differences.…”

Preventing all‐cause hospitalizations in type 2 diabetes with sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: A narrative review and proposed clinical approach

“…Specifically, some GLP-1RAs protect from MACE (usually composed of cardiovascular death or nonfatal stroke or myocardial infarction) 21,23,25,26,30 and SGLT2 inhibitors reduce hHF and improve kidney outcomes. 9,[13][14][15][16][17][18][19][27][28][29]36 Some evidence indicates that specific SGLT2 inhibitors also reduce MACE rate 9,14,37 and GLP-1RAs reduce proteinuria and may improve kidney outcomes in T2D. 22,24,[38][39][40] GLP-1RAs were also shown to increase the likelihood of nonalcoholic steatohepatitis resolution.…”