Differential effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and renal outcomes according to renal function: a dose-response meta-analysis involving 10 randomized clinical trials and 71 553 individuals.

BACKGROUND: The main target of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the sodium-glucose cotransporters 2, is found in the kidneys, and their activity is reduced in patients with chronic kidney disease (CKD). How the efficacy of SGLT2i may vary in patients with different levels of renal impairment has not been fully elucidated. METHODS: We searched the PubMed databases for relevant studies published through May 25, 2022. Randomized control trials comparing SGLT2i with placebo and reporting cardiovascular or renal outcomes were included. The primary outcome was the composite of major adverse cardiovascular events (MACE), which were defined as cardiovascular death (CV death), nonfatal myocardial infarction (MI), and nonfatal ischemic stroke. Secondary outcomes included the components of MACE, all-cause mortality, hospitalization for heart failure (HHF), the composite of CV death and HHF, and composite renal outcomes. Linear meta-regression analysis was used to assess the effects of estimated glomerular filtration rate (eGFR) on the risks associated with SGLT2i treatment vs placebo for all outcomes. Nonlinear meta-regression analysis was also performed for MACE to investigate the combined influence of reduced drug efficacy in CKD but possible greater risk reduction in a population with higher risk at baseline. Further analyses were performed by including additional study-level covariates, including the prevalence of diabetes mellitus (DM), heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD). RESULTS: Risk ratios for MACE, CV death, nonfatal MI, HHF, and composite renal outcomes associated with SGLT2i treatment were not significantly related to baseline eGFR values. A positive association was observed between eGFR values and the risk of stroke with SGLT2i use (regression coefficient ß = .0109, 95% confidence interval [CI] 0.0029-0.0188). A similar positive association was observed between eGFR values and the composite outcome of CV death and HHF (ß = .0025, 95% CI 0.0000-0.0051). The results of the meta-regression analyses, including the additional covariates of DM, HF, and ASCVD, were consistent with the results of the primary analyses for most outcomes. CONCLUSION: The protective effects of SGLT2i for reducing most adverse cardiovascular and renal outcomes persisted in patients with variable degrees of renal impairment. The observed benefits such as preventing CV death, HF worsening, or stroke may be greater for patients with more severe CKD. Considering the cardiovascular and renal benefits associated with SGLT2i treatment, patients with CKD should be treated aggressively to improve outcomes. PROSPERO REGISTRATION NUMBER: CRD42021273500.

Major adverse cardiovascular and limb events in people with diabetes treated with GLP-1 receptor agonists vs SGLT2 inhibitors.

AIMS/HYPOTHESIS: This study aimed to assess the real-world outcomes of people with diabetes mellitus treated with glucagon-like peptide-1 receptor agonists (GLP1RAs) compared with those treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in terms of major adverse cardiovascular and limb events. Peripheral artery disease is a common cause of morbidity in people with diabetes. Previous cardiovascular outcome trials have demonstrated the benefits of GLP1RAs and SGLT2is for reducing various cardiovascular events, but the safety and efficacy of these drugs on limb outcomes remain subject to debate and ambiguity. METHODS: A retrospective cohort study was conducted in which data were collected from the Taiwan National Health Insurance Research Database. In total, 379,256 individuals with diabetes receiving either GLP1RA or SGLT2i with treatment initiated between 1 May 2016 and 31 December 2019 were identified. The primary outcome was major adverse limb events (MALE), defined as the composite of newly diagnosed critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for peripheral artery disease, and non-traumatic amputation. The secondary outcome was major adverse cardiac events, which was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Other examined outcomes included death from any cause and hospitalisation for heart failure. Propensity score matching was performed at a 1:4 ratio between the GLP1RA and SGLT2i groups to mitigate possible selection bias. RESULTS: A total of 287,091 patients were eligible for analysis, with 81,152 patients treated with SGLT2i and 20,288 patients treated with GLP1RA after matching. The incidence of MALE was significantly lower in the GLP1RA group than in the SGLT2i group (3.6 vs 4.5 events per 1000 person-years; subdistribution HR 0.80; 95% CI 0.67, 0.96), primarily due to a lower incidence of critical limb ischaemia. The reduced risks of MALE associated with GLP1RA use were particularly noticeable in people with diabetic peripheral neuropathy (subdistribution HR 0.66 vs 1.11; p for interaction 0.006). CONCLUSIONS/INTERPRETATION: In people with diabetes, GLP1RA use was associated with significantly reduced risks of MALE compared with SGLT2i within the first 2 years after initiation, especially among people with diabetic neuropathy.