PMID- 34636161 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 2398-9238 (Electronic) IS - 2398-9238 (Linking) VI - 5 IP - 1 DP - 2022 Jan TI - Benefits and harms of sodium-glucose co-transporter-2 inhibitors (SGLT2-I) and renin-angiotensin-aldosterone system inhibitors (RAAS-I) versus SGLT2-Is alone in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. PG - e00303 LID - 10.1002/edm2.303 [doi] LID - e00303 AB - INTRODUCTION: It is uncertain if the combination of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and renin-angiotensin-aldosterone system inhibitors (RAAS-Is) provides better cardio-renal clinical outcomes in people with type 2 diabetes mellitus (T2DM) compared with SGLT2-Is alone. Using a systematic review and meta-analysis of randomized controlled trials (RCTs), we evaluated the efficacy and safety with respect to cardio-renal outcomes of the combination of SGLT2 and RAAS inhibitors vs SGLT2-Is in patients with T2DM. METHODS: Studies were identified from MEDLINE, Embase, the Cochrane Library and search of bibliographies to May 2021. The Cochrane risk of bias tool was used to assess the risk of bias of each study. Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. Quality of the evidence was assessed using GRADE. RESULTS: Nine articles comprising 8 RCT evaluations (n = 34,551 participants) that compared SGLT2-Is with placebo in patients with T2DM against a background of standard care and reported subgroup results for those treated with or without RAAS-Is at baseline were included. No RCT specifically investigated the combination of SGLT2 and RAAS inhibitors compared with SGLT2-Is alone. The RRs (95% CIs) for composite cardiovascular outcome and composite CVD death/heart failure hospitalization comparing SGLT2-Is vs placebo in patients on RAAS-Is were 0.93 (0.85-1.01) and 0.88 (0.76-1.02), respectively. The corresponding estimates for patients not on RAAS-Is were 0.78 (0.65-0.93) and 0.73 (0.65-0.82), respectively. There was no evidence of interactions between RAAS-I status and the effects of SGLT2-Is for both outcomes. Single study results showed that SGLT2-Is vs placebo reduced the risk of composite kidney outcome and cardiovascular death in patients with RAAS inhibition. The effect of SGLT2 inhibition vs placebo on kidney parameters, genital infections, volume depletion, hyperkalaemia, hypokalaemia, hypoglycaemia and other adverse events was similar in patients with or without RAAS inhibition. The quality of the evidence ranged from very low to moderate. CONCLUSIONS: Aggregate published data suggest that the combination of SGLT2 and RAAS inhibitors in the treatment of patients with T2DM may be similar in efficacy and safety if not superior to SGLT2-Is alone. Head-to-head comparisons of the two interventions are warranted to inform T2DM management. The use of SGLT2 inhibition as a first-line therapy in T2DM or its early use in the prevention of renal deterioration and cardiovascular complications in addition to its glycaemic control deserves further study. CI - (c) 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd. FAU - Seidu, Samuel AU - Seidu S AUID- ORCID: 0000-0002-8335-7018 AD - Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK. FAU - Kunutsor, Setor K AU - Kunutsor SK AUID- ORCID: 0000-0002-2625-0273 AD - National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK. AD - Translational Health Sciences, Bristol Medical School, Learning & Research Building (Level 1), University of Bristol, Southmead Hospital, Bristol, UK. FAU - Topsever, Pinar AU - Topsever P AD - Department of Family Medicine, Acibadem Mehmet Ali Aydinlar University School of Medicine, Kerem Aydinlar Campus, Atasehir, Turkey. FAU - Khunti, Kamlesh AU - Khunti K AD - Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK. LA - eng GR - DH_/Department of Health/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20211012 PL - England TA - Endocrinol Diabetes Metab JT - Endocrinology, diabetes & metabolism JID - 101732442 RN - 0 (Hypoglycemic Agents) RN - 0 (Sodium-Glucose Transporter 2) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 9NEZ333N27 (Sodium) RN - IY9XDZ35W2 (Glucose) SB - IM MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Glucose/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Randomized Controlled Trials as Topic MH - Renin-Angiotensin System MH - Sodium/therapeutic use MH - Sodium-Glucose Transporter 2/therapeutic use MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use PMC - PMC8754244 OTO - NOTNLM OT - RAAS inhibitor OT - SGLT2 inhibitor OT - Type 2 diabetes COIS- Dr. Khunti reports personal fees from Amgen, personal fees from Astrazeneca, personal fees from Bayer, personal fees from NAPP, personal fees from Lilly, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Roche, personal fees from Berlin-Chemie AG / Menarini Group, personal fees from Sanofi-Aventis, personal fees from Servier, personal fees from Boehringer Ingelheim, grants from Pfizer, grants from Boehringer Ingelheim, grants from AstraZeneca, grants from Novartis, grants from Novo Nordisk, grants from Sanofi-Aventis, grants from Lilly, grants from Merck Sharp & Dohme, grants from Servier, outside the submitted work. Dr. Seidu reports personal fees from Amgen, personal fees from Astrazeneca, personal fees from NAPP, personal fees from Lilly, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Roche, personal fees from Sanofi-Aventis, personal fees from Boehringer Ingelheim, grants from AstraZeneca, grants from Sanofi-Aventis, grants from Servier, grants from Janssen, outside the submitted work. Dr Kunutor has no conflicts to report. Dr Topsever has received educational sponsorship or honoraria for speaking at meetings or serving at Advisory Boards from Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi Aventis. EDAT- 2021/10/13 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/10/12 CRDT- 2021/10/12 07:02 PHST- 2021/09/19 00:00 [revised] PHST- 2021/08/27 00:00 [received] PHST- 2021/09/21 00:00 [accepted] PHST- 2021/10/13 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/10/12 07:02 [entrez] PHST- 2021/10/12 00:00 [pmc-release] AID - EDM2303 [pii] AID - 10.1002/edm2.303 [doi] PST - ppublish SO - Endocrinol Diabetes Metab. 2022 Jan;5(1):e00303. doi: 10.1002/edm2.303. Epub 2021 Oct 12.