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    Comparative Efficacy of Five SGLT2i on Cardiorenal Events: A Network Meta-analysis Based on Ten CVOTs. Qiu Mei,Ding Liang-Liang,Zhou Hai-Rong American journal of cardiovascular drugs : drugs, devices, and other interventions BACKGROUND:The relative efficacy of different sodium-glucose transporter 2 inhibitors (SGLT2i) on cardiorenal outcomes is unclear. METHODS:We included cardiovascular outcome trials (CVOTs) of SGLT2i. The eight endpoints of interest were major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular death (CVD), CVD or hospitalization for heart failure (HHF), HHF, kidney function progression (KFP), and all-cause death (ACD). We conducted a Bayesian network meta-analysis and calculated the surface under the cumulative ranking curve (SUCRA) probability to rank treatments. RESULTS:We included ten CVOTs involving five SGLT2i. Canagliflozin (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.53-0.77), dapagliflozin (HR 0.70; 95% CI 0.62-0.79), empagliflozin (HR 0.68; 95% CI 0.59-0.78), ertugliflozin (HR 0.70; 95% CI 0.54-0.90), and sotagliflozin (HR 0.66; 95% CI 0.56-0.77) versus placebo reduced HHF, whereas none reduced MI and stroke. Empagliflozin reduced CVD or HHF (HR 0.81; 95% CI 0.67-0.99) and KFP (HR 0.65; 95% CI 0.45-0.93), and dapagliflozin reduced KFP (HR 0.69; 95% CI 0.52-0.92), versus ertugliflozin. Canagliflozin had the greatest SUCRA values for the reduction of MACE, stroke, and HHF, whereas empagliflozin had the greatest SUCRA values for the reduction of MI, CVD, CVD or HHF, KFP, and ACD. CONCLUSIONS:Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin versus placebo reduce HHF but none reduces MI and stroke. Canagliflozin is most effective in reducing MACE and HHF, and empagliflozin is most effective in reducing CVD, CVD or HHF, KFP, and ACD. These findings will guide the use of specific SGLT2i in the prevention of different cardiorenal events. 10.1007/s40256-021-00484-8
    Gliflozins for the prevention of stroke in diabetes and cardiorenal diseases: A meta-analysis of cardiovascular outcome trials. Zhao Li-Min,Huang Jia-Nan,Qiu Mei,Ding Liang-Liang,Zhan Ze-Lin,Ning Jie Medicine BACKGROUND:Individual randomized trials are not powered to assess the relationship between use of sodium-glucose transporter 2 inhibitors and risk of stroke. We sought to explore this issue by a meta-analysis incorporating relevant trials including several latest trials. METHODS:Cardiovascular outcome trials of gliflozins were included. Primary outcome was stroke, while secondary outcome was major adverse cardiovascular events (MACE), which was a composite of stroke, myocardial infarction, or cardiovascular death. Meta-analysis was conducted stratified by with/without chronic kidney disease (CKD), with/without heart failure (HF), and with/without atherosclerotic cardiovascular disease (ASCVD), and stratified by different gliflozins. RESULTS:We included 9 trials in this meta-analysis. Compared with placebo, gliflozins significantly lowered stroke (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.55-0.84) and MACE (HR 0.77, 95% CI 0.69-0.86) in type 2 diabetes (T2D) patients with CKD, but did not significantly affect stroke (HR 1.00, 95% CI 0.86-1.16) and MACE (HR 0.94, 95% CI 0.86-1.02) in T2D patients without CKD. Gliflozins had no significant effects on the stroke risk (HR 0.94, 95% CI 0.82-1.07) in T2D patients regardless of HF status (Psubgroup = .684) and ASCVD status (Psubgroup = .915), but significantly lowered MACE (HR 0.89, 95% CI 0.83-0.96) in T2D patients regardless of HF status (Psubgroup = .428) and ASCVD status (Psubgroup = .423). Canagliflozin (HR 0.84, 95% CI 0.69-1.01) showed the trend of a reduction in the stroke risk versus placebo, and sotagliflozin (HR 0.73, 95% CI 0.54-0.98) significantly lowered the stroke risk; whereas the other 3 gliflozins did not significantly affect that risk. Ertugliflozin (HR 0.97, 95% CI 0.85-1.11) had no significant effects on the MACE risk, whereas the other 4 gliflozins significantly lowered that risk. CONCLUSIONS:Gliflozins, especially canagliflozin and sotagliflozin, should be recommended in T2D patients with CKD to prevent stroke. Most gliflozins lower the risk of MACE in T2D patients regardless of HF status and ASCVD status, whereas ertugliflozin is not observed to lower that risk. 10.1097/MD.0000000000027362
    Do SGLT2 Inhibitors Improve Cardio-Renal Outcomes in Patients With Type II Diabetes Mellitus: A Systematic Review. Kalluri Sahithi Reddy,Bhutta Tinaz H,Hannoodee Hanan,Al Khalili Mahmoud,Theik Nyein Wint Yee,Raji Oluwatimilehin E,Shenwai Priya,Shah Rutul,Khan Safeera Cureus Diabetes mellitus (DM) is associated with dreadful changes in the cardiovascular and renal systems, causing increased morbidity and mortality. Sodium-glucose cotransport-2 (SGLT2) inhibitors belong to the oral hypoglycemic group of drugs believed to reduce these events by various mechanisms in DM. We performed a systematic review to determine the effectiveness of SGLT2 inhibitors in reducing cardiovascular and renal complications and address safety concerns in participants with type 2 diabetes mellitus (T2DM). We explored PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane library, and ResearchGate for randomized controlled trials and observational studies done on the advantages of SGLT2 inhibitors in the prevention or reduction of worsening cardiovascular and renal changes in T2DM. Studies were screened for the quality assessment using the Cochrane risk-of-bias assessment tool and Newcastle-Ottawa scale. We screened 5615 articles, out of which 22 articles with 7,02,977 diabetes mellitus patients treated with SGLT2 inhibitors were used for the systematic review after meticulously filtering articles based on inclusion and exclusion criteria. The trials included one of the following drugs - empagliflozin, dapagliflozin, canagliflozin, and luseogliflozin. SGLT2 inhibitors significantly reduced the risk of heart failure (HF), frequency of hospitalizations due to HF, all-cause mortality, cardiovascular mortality, and nonfatal myocardial infarction. Renal outcomes showed a significant lowering of risk of acute kidney failure, progression of chronic kidney disease, renal mortality, and improvement in urinary albumin creatinine ratio. We noticed an initial worsening of the estimated glomerular filtration rate followed by stabilizing and reaching the baseline on long-term treatment, especially in end-stage renal failure patients. The review showed that SGLT2 inhibitors have adverse reactions similar to that of a placebo, with a slight increase in treatable genital mycotic and urinary tract infections but no evidence of diabetic ketoacidosis, fractures, and amputations. According to the available data, SGLT2 inhibitors can significantly prevent or reduce cardiovascular diseases and kidney abnormalities in patients with type 2 diabetes mellitus with tolerable safety outcomes. 10.7759/cureus.17668
    Long-term renal outcomes associated with sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Zhang Xiaodan,Zhong Zhen,Li Yanli,Li Wangen Diabetes/metabolism research and reviews AIMS:The long-term impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on renal functions remains undefined. This study was undertaken to investigate the renal outcomes associated with SGLT2 inhibitors in patients with type 2 diabetes (T2DM) in the long term. METHODS:A systematic literature search of PubMed and ClinicalTrials.gov was conducted. Randomized controlled trials which reported renal outcomes at the study endpoint in patients with T2DM receiving treatments of SGLT2 inhibitors were included. Renal adverse events were determined using prespecified lists from the Medical Dictionary for Regulatory Activities or laboratory values. Odds ratio with 95% confidence interval (CI) was used for assessment of dichotomous data. The mean difference or standardized mean difference with 95% CI was used for assessment of continuous data. Random effects models were adopted to measure the pooled outcomes. RESULTS:Thirty-nine studies involving 35 trials were identified. Compared with placebo or other anti-diabetic medications, SGLT2 inhibitors were associated with significant lower incidence of composite renal outcome and acute renal failure or injury in patients with T2DM. The risk of progression of albuminuria also appeared to be decreased. No significant changes of estimated glomerular filtration rate levels or urine albumin-creatinine ratios were found in patients receiving SGLT2 inhibitors. CONCLUSIONS:Overall renal safety and beneficial effects are indicated for SGLT2 inhibitors. Further confirmative data from large trials and real-world studies are needed. 10.1002/dmrr.3303
    The safety outcomes of sodium-glucose cotransporter 2 inhibitors in patients with different renal function: A systematic review and meta-analysis. Bai Yaling,Jin Jingjing,Zhou Wei,Zhang Shenglei,Xu Jinsheng Nutrition, metabolism, and cardiovascular diseases : NMCD AIMS:We aimed to assess whether the safety outcomes exerted by sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with different renal function at baseline. DATA SYNTHESIS:We searched randomized controlled trials comparing SGLT2 inhibitors with placebo in participants simultaneously involving the entire range of estimated glomerular filtration rate (eGFR) levels at baseline in one study. According to eGFR, we divided the population into two subgroups with eGFR <60 ml/min/1.73 m and eGFR≥60 ml/min/1.73 m. Data from the CANVAS program, CREDENCE, EMPA-REG OUTCOME, DECLARE-TIMI 58, DAPA-HF, and EMPA-REG RENAL were included. SGLT2 inhibitors significantly reduced the risk of all serious adverse events (HR 0.91 [95% CI 0.87 to 0.95], p < 0.001) and acute kidney injury (HR 0.74 [95% CI 0.64 to 0.85], p < 0.001). Except for high risk of genital infection, SGLT2 inhibitors did not increase the risk of amputation, fracture, hyperkalemia, hypoglycemia, volume depletion, or urinary tract infection. Further analyses showed that these safety outcomes were similar between subgroups (p-interaction > 0.05). For osmotic diuresis, SGLT2 inhibitors significantly increased the risk by 75% (p = 0.036), and subgroup analyses showed that this effect was completely attributed to the increase in patients with eGFR ≥60 ml/min/1.73 m (p-interaction<0.001). CONCLUSION:The indication of no risk of osmotic diuresis in patients with eGFR<60 ml/min/1.73 m and the consistency of other safety outcomes across different baseline renal function may allow additional individuals to safely use SGLT2 inhibitors. 10.1016/j.numecd.2021.02.006
    Meta-Analysis on the Safety and Cardiorenal Efficacy of SGLT2 Inhibitors in Patients Without T2DM. Li Lu-Feng,Ding Liang-Liang,Zhan Ze-Lin,Qiu Mei Frontiers in cardiovascular medicine The cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) are established, whereas those in patients without T2DM are not established. We sought to assess the cardiorenal efficacy and safety of SGLT2 inhibitors in non-T2DM patients by performing a meta-analysis based on the subgroup data of non-T2DM patients from relevant secondary analysis articles in which subgroup analyses were done according to the status of diabetes. Compared to placebo, SGLT2 inhibitors significantly reduced heart failure hospitalization [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.59-0.83] and kidney-specific composite outcome (RR 0.55, 95% CI 0.40-0.75) and increased Kansas City Cardiomyopathy Questionnaire total score by 1.15 (95% CI 1.05-1.25) in patients without T2DM with heart failure (HF) or chronic kidney disease (CKD), whereas gliflozins did not significantly affect cardiovascular death, all-cause mortality, volume depletion, fracture, and amputation in this vulnerable population. There was no event of major hypoglycemia or diabetic ketoacidosis observed in the non-T2DM subgroup in included trials. These findings will further prompt gliflozins to be used for the prevention of HF and renal failure events and for the improvement of life quality in patients without T2DM with HF or CKD. 10.3389/fcvm.2021.690529
    SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Zannad Faiez,Ferreira João Pedro,Pocock Stuart J,Anker Stefan D,Butler Javed,Filippatos Gerasimos,Brueckmann Martina,Ofstad Anne Pernille,Pfarr Egon,Jamal Waheed,Packer Milton Lancet (London, England) BACKGROUND:Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS:We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS:Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION:The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING:Boehringer Ingelheim. 10.1016/S0140-6736(20)31824-9
    Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. Menne Jan,Dumann Eva,Haller Hermann,Schmidt Bernhard M W PLoS medicine BACKGROUND:Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI). METHODS AND FINDINGS:We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III). CONCLUSIONS:SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported. 10.1371/journal.pmed.1002983
    SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Neuen Brendon L,Young Tamara,Heerspink Hiddo J L,Neal Bruce,Perkovic Vlado,Billot Laurent,Mahaffey Kenneth W,Charytan David M,Wheeler David C,Arnott Clare,Bompoint Severine,Levin Adeera,Jardine Meg J The lancet. Diabetes & endocrinology BACKGROUND:The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. METHODS:We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). FINDINGS:From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52-0·86, p=0·0019), an effect consistent across studies (I=0%, p=0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53-0·81, p<0·0001), and acute kidney injury (0·75, 0·66-0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (p=0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m (RR 0·70, 95% CI 0·54-0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (p=0·66) and use of RAS blockade (p=0·31). INTERPRETATION:SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. FUNDING:None. 10.1016/S2213-8587(19)30256-6
    SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Zelniker Thomas A,Wiviott Stephen D,Raz Itamar,Im Kyungah,Goodrich Erica L,Bonaca Marc P,Mosenzon Ofri,Kato Eri T,Cahn Avivit,Furtado Remo H M,Bhatt Deepak L,Leiter Lawrence A,McGuire Darren K,Wilding John P H,Sabatine Marc S Lancet (London, England) BACKGROUND:The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined. METHODS:We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function. FINDINGS:We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline. INTERPRETATION:SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. FUNDING:None. 10.1016/S0140-6736(18)32590-X
    Effects of SGLT2 inhibitors on cardiovascular death and all-cause death in patients with type 2 diabetes and chronic kidney disease: an updated meta-analysis including the SCORED trial. Therapeutic advances in endocrinology and metabolism BACKGROUND:The effects of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiovascular death (CV death) and all-cause death (AC death) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are currently under intensive investigation. We intended to conduct an updated meta-analysis including the SCORED trial to evaluate the effects of SGLT2 inhibitors on death and cardiorenal events in this vulnerable population. METHODS:Cardiorenal outcome trials of SGLT2 inhibitors were included. Primary outcomes were CV death and AC death, while secondary outcomes were hospitalization for heart failure (HHF), myocardial infarction (MI), CKD progression, cardiovascular death or hospitalization for heart failure (CV death or HHF), major adverse cardiovascular events (MACE), and stroke. Meta-analysis was conducted for each outcome. RESULTS:Eight trials were included for meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of CV death (HR = 0.86, 95% CI = 0.75-0.98), AC death (HR = 0.87, 95% CI = 0.79-0.96), HHF (HR = 0.64, 95% CI = 0.56-0.74), MI (HR = 0.76, 95% CI = 0.65-0.89), CKD progression (HR = 0.62, 95% CI = 0.54-0.72), and CV death or HHF (HR = 0.73, 95% CI = 0.67-0.80). No heterogeneity existed in the above meta-analyses (all I values = 0%), whereas moderate heterogeneity existed in the meta-analyses for MACE and stroke (I = 31.6% and 44.5%, respectively). CONCLUSIONS:Our findings suggest that SGLT2 inhibitors versus placebo significantly lower death, heart failure, renal failure, and MI events in patients with T2D and CKD. Head-to-head trials are needed to examine the possible differences in the effects of various gliflozins on MACE and stroke. 10.1177/20420188211044945
    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. Seidu Samuel,Kunutsor Setor K,Topsever Pinar,Khunti Kamlesh Endocrinology, diabetes & metabolism 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. 10.1002/edm2.303
    Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. Qiu Mei,Ding Liang-Liang,Zhang Miao,Zhou Hai-Rong Diabetes & vascular disease research There are no relevant meta-analyses that have assessed the safety of the sodium-glucose transporter 2 (SGLT2) inhibitors in different chronic diseases. We aimed at evaluating the safety of four SGLT2 inhibitors in three chronic diseases by meta-analysis of the large randomized trials of SGLT2 inhibitors. We performed random-effects meta-analysis and carried out subgroup analysis according to type of underlying diseases and type of SGLT2 inhibitors. SGLT2 inhibitors versus placebo significantly reduced the risk of acute kidney injury (RR 0.75, 95% CI 0.66-0.85), and showed the reduced trend in the risk of severe hypoglycemia (RR 0.86, 95% CI 0.71-1.03). SGLT2 inhibitors significantly increased the risks of diabetic ketoacidosis (RR 2.57), genital infection (RR 3.75), and volume depletion (RR 1.14); and showed the increased trends in the risks of fracture (RR 1.07), amputation (RR 1.21), and urinary tract infection (RR 1.07). These effects exhibited by SGLT2 inhibitors were consistent across three chronic diseases (i.e. type 2 diabetes, chronic heart failure, and chronic kidney disease) and four SGLT2 inhibitors (i.e. dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin) (all  > 0.05). These findings will guide that specific adverse events are monitored when SGLT2 inhibitors are used in clinical practice. 10.1177/14791641211011016
    Kidney outcomes using a sustained ≥40% decline in eGFR: A meta-analysis of SGLT2 inhibitor trials. Cherney David Z I,Dagogo-Jack Samuel,McGuire Darren K,Cosentino Francesco,Pratley Richard,Shih Weichung J,Frederich Robert,Maldonado Mario,Liu Jie,Wang Shuai,Cannon Christopher P, Clinical cardiology BACKGROUND:A recent meta-analysis of sodium-glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials. HYPOTHESIS:The apparent heterogeneity of the meta-analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials. METHODS:We performed a meta-analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE-TIMI 58 (NCT01730534), and EMPA-REG OUTCOME (NCT01131676). RESULTS:Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51-0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I  = 0.0%). CONCLUSIONS:Our meta-analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors. 10.1002/clc.23665
    Cardiovascular Outcome in Patients Treated With SGLT2 Inhibitors for Heart Failure: A Meta-Analysis. Gager Gloria M,Gelbenegger Georg,Jilma Bernd,von Lewinski Dirk,Sourij Harald,Eyileten Ceren,Filipiak Krzysztof,Postula Marek,Siller-Matula Jolanta M Frontiers in cardiovascular medicine Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs that have become increasingly relevant for the treatment and prevention of heart failure (HF). Therefore, we aimed to investigate various SGLT2 inhibitors in patients with established HF at baseline and focused on the different types of HF. An extensive search of PubMed and Web of Science until January 2021 was done. Two reviewers, independently and in duplicate, applied the selection criteria. This meta-analysis was conducted according to the PRISMA guidelines. Data were pooled using a random-effects model. Randomized controlled trials (RCTs) of SGLT2 inhibitors vs. a comparator in patients with HF reporting clinical outcomes were included. The primary efficacy outcome was the composite of hospitalization for HF (HHF) or cardiovascular (CV) mortality. All-cause mortality, CV mortality, and HHF were considered as secondary endpoints. Subgroup analyses involving the status of diabetes, type of HF, administered type of SGLT2 inhibitor, sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), cause of HF, and concomitant medication were performed. Seventeen RCTs, comprising a total of 20,749 participants, were included ( = 10,848 treated with SGLT2 inhibitors and = 9,901 treated with a comparator). Treatment with SGLT2 inhibitors in a HF population was associated with a 27% relative risk reduction (RRR) of HHF or CV mortality [risk ratio (RR) = 0.73, 95% CI = 0.68-0.78], 32% RRR of HHF (RR = 0.68, 95% CI = 0.62-074), 18% RRR of CV mortality (RR = 0.82, 95% CI = 0.73-0.91), and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75-0.91). The effect of SGLT2 inhibitors on the primary endpoint was consistent among the different gliflozines. The effect of SGLT2 inhibitors on the primary endpoint was independent of underlying diabetes mellitus, age, sex, BMI, renal function, and HF type. SGLT2 inhibitors are associated with improved CV outcomes in patients with HF. 10.3389/fcvm.2021.691907
    SGLT2 inhibitors and cardiovascular and renal outcomes: a meta-analysis and trial sequential analysis. Heart failure reviews Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events and renal outcomes in patients with diabetes mellitus (DM). This meta-analysis aimed to provide a thorough evaluation regarding the efficacy and safety of SGLT2 inhibitors. Data search of MEDLINE/PubMed, Embase, and Cochrane Library databases and ClinicalTrials.com from inception through November 26, 2020. We included randomized trials, SGLT2 inhibitors compared with placebo, patients with or without diabetes at recruitment, and reporting the incidence of cardiovascular or renal outcomes. Two authors extracted pertinent data into predefined data collection tables. Ten trials were included (71,553 patients). The mean age was 64.7 ± 8.4 years, with 65.1% male. Follow-up durations range 9-50 months. Inhibition of SGLT2 resulted in lower composite outcome of heart failure (HF) hospitalization or cardiovascular death (RR 0.76, 95% CI 0.73-0.81, P < 0.01) and lower risk of renal outcomes (RR 0.68, 95% CI 0.60-0.77, P < 0.01). Furthermore, SGLT2 inhibitors were associated with lower major adverse cardiovascular events (MACEs), HF hospitalization, cardiovascular mortality, all-cause mortality, myocardial infarction, and serious adverse events, compared with placebo (P < 0.05). Sensitivity analyses revealed lower MACE events also in patients with HF, and a lower HF hospitalization and cardiovascular mortality in non-diabetic patients (P < 0.05). While the amputation risk was comparable between the two groups, the risk of diabetic ketoacidosis was higher in the SGLT2 inhibitor group. Inhibition of SGLT2 in patients with DM and prevalent ASCVD reduces the risk of HF hospitalization, cardiovascular mortality, all-cause mortality, MACE, and renal outcomes without increasing the risk of serious adverse events or amputation. 10.1007/s10741-021-10083-z
    Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis. American journal of kidney diseases : the official journal of the National Kidney Foundation RATIONALE & OBJECTIVE:An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN:Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS:Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES:Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH:For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS:Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS:Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS:These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN. 10.1053/j.ajkd.2021.03.007
    Sodium-glucose cotransporter 2 inhibitors benefit to kidney and cardiovascular outcomes for patients with type 2 diabetes mellitus and chronic kidney disease 3b-4: A systematic review and meta-analysis of randomized clinical trials. Diabetes research and clinical practice BACKGROUND:A systematic review and meta-analysis was performed to assess the kidney and cardiovascular (CV) outcomes of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stage 3b-4. METHOD:We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs). Medline, Embase, and the Cochrane Central were searched for available trials up to Jan 18, 2021. RESULTS:From identifying 1892 citations, we included nine studies into quantitative analyses with a total of 6521 participants. In the patients with T2DM and CKD stage 3b-4, SGLT2 inhibitors significantly decreased the risk of the primary kidney outcome (HR 0.65, 95% CI 0.55-0.76) and slowed the decline in eGFR slope with a difference between treatment and control of 0.46 ml/min/1.73 m2 per year (95% CI 0.37-0.55). SGLT2 inhibitors also reduced the risk of the major adverse cardiovascular events (MACE) (HR 0.75, 95% CI 0.60-0.93). CONCLUSIONS:SGLT2 inhibitors can reduce the risk of kidney disease and MACE outcomes for patients with T2DM and CKD stage 3b-4, which may be the most beneficial effects observed in the included trials. 10.1016/j.diabres.2021.109033
    The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Piperidou Alexia,Sarafidis Pantelis,Boutou Afroditi,Thomopoulos Costas,Loutradis Charalampos,Alexandrou Maria Eleni,Tsapas Apostolos,Karagiannis Asterios Journal of hypertension : Diabetic kidney disease is a serious microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease in western countries. New therapeutic agents are needed to delay its onset and progression. Recent literature suggests that sodium-glucose cotransporter 2 (SGLT-2) inhibitors may have renoprotective effects. Our aim was to systematically review the effect of SGLT-2 inhibitors on albuminuria and proteinuria in patients with diabetes mellitus. Studies were identified by search in major electronic databases, clinical trial registers, and sources of gray literature. We included randomized controlled trials of currently approved SGLT-2 inhibitors with a duration of at least 12 weeks. The primary outcome was the between-groups difference in the proportional (%) change of albuminuria or proteinuria between baseline and end of treatment. SGLT-2 inhibitors were associated with statistically significant reduction in albuminuria compared to placebo or active control [weighted mean difference (WMD) -25.39%, 95% confidence interval (CI) -34.17 to -16.62] (15 studies, N = 17 540 patients). When trials were stratified according to the level of baseline albuminuria, reduction in urine albumin-to-creatinine ratio was more prominent in randomized controlled trials in patients with moderately (WMD -40.78%, 95% CI -63.21 to -18.34) or severely increased albuminuria (WMD -36.40%, 95% CI -51.53 to -21.26). Only one study reported data for urine protein-to-creatinine ratio. Finally, SGLT-2 inhibitors reduced systolic and diastolic blood pressure by 4.43 mmHg (95% CI -5.24 to -3.63) and 1.81 mmHg (95% CI -2.38 to -1.23), respectively. 10.1097/HJH.0000000000002050
    Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials. Dicembrini Ilaria,Tomberli Benedetta,Nreu Besmir,Baldereschi Giorgio Iacopo,Fanelli Fabrizio,Mannucci Edoardo,Monami Matteo Diabetes research and clinical practice BACKGROUND:Concerns have been raised on the risk of lower limb amputations with SGLT-2 inhibitors. Aim of the present metanalysis is the assessment of the effect of SGLT-2inhibitors on peripheral artery disease and lower limb amputations in randomized controlled trials performed in patients with type 2 diabetes. METHODS:A Medline and Embase search for "Canaglifozin" OR "Dapaglifozin" OR "Empaglifozin" OR "Ertuglifozin" OR "Ipraglifozin" OR Tofoglifozin" OR "Luseoglifozin" was performed, collecting randomized clinical trials (duration > 12 weeks) up to December 1st, 2018, comparing SGLT-2i at approved dose with placebo or other active comparators different from SGLT-2 inhibitors. Furthermore, unpublished studies were searched in the www.clinicaltrials.gov register. Separate analyses were performed for individual molecules of the class. In addition, a separate analysis was performed for placebo-controlled trials. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes defined above. RESULTS:A total of 27 trials fulfilling the inclusion criteria was identified. The overall incidence of peripheral artery disease was increased with SGLT-2 inhibitors (MH-OR: 1.26 [1.04, 1.52]). The increase of risk was statistically significant only with canagliflozin. MH-OR for amputation in the three cardiovascular safety trials with SGLT-2 inhibitors was 1.22 [0.59-2.52]. CONCLUSIONS:At present, there is no reason to believe that empagliflozin or dapagliflozin increase the risk of either peripheral artery disease of lower limb amputations. Canagliflozin could be associated with a specific risk, which needs to be further investigated. 10.1016/j.diabres.2019.05.028
    Efficacy and safety of dapagliflozin as monotherapy in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Feng Miao,Lv Haihong,Xu Xia,Wang Jue,Lyu Wenyi,Fu Songbo Medicine BACKGROUND:Dapagliflozin, a novel inhibitor of sodium-glucose cotransporter-2 (SGLT-2), lowers blood glucose level by specifically inhibiting the activity of SGLT-2. Previous studies showed efficacy and safety of dapagliflozin combined with other antihyperglycemic agents in type 2 diabetes (T2DM), however, there are few studies for dapagliflozin as monotherapy. The aim of this study was to assess the efficacy and safety of dapagliflozin as a monotherapy in T2DM and provide theoretical basis for clinical rational use of drugs. METHODS:We did a systematic review and meta-analysis of randomized, placbo-controlled clinical studies in patients with type 2 diabetes. We searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP database through October 2018, we also manually screened list of references to the previous meta-analysis of dapagliflozin in the treatment of type 2 diabetes. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. A meta-analysis was conducted by using RevMan 5.3 software. RESULTS:Six randomized controlled trials (RCTs) including 2033 patients were analyzed. Compared with placebo, dapagliflozin monotherapy was associated with a reduction in glycosylated hemoglobin A1c (HbA1c) (weighted mean difference [WMD]: -0.60%; 95% confidence interval [CI]: -0.67%, -0.52%; P < .00001), fasting plasam glucose (FPG) (WMD: -1.30 mmol/L; 95% CI: -1.52, -1.08; P < .00001), and body weight (WMD: -1.50 kg; 95% CI: -1.67, -1.32; P < .00001). Dapagliflozin was associated with an increased risk of urinary tract infections (relative risk [RR]: 1.74; 95% CI: 1.21, 2.49; P = .003) and genital tract infections (RR: 3.52; 95% CI: 2.06, 6.03; P < .00001). CONCLUSIONS:Dapagliflozin monotherapy was well tolerated and effective in reducing the level of HbA1c, FPG, and body weight in patients with T2DM without increasing hypoglycaemia, although it may increase the risk of urinary tract infections and genital tract infections. This meta-analysis provides an evidence for the treatment in patients with T2DM. However, more randomized clinical evidences are still needed to verify the results. 10.1097/MD.0000000000016575
    Nephrolithiasis and sodium-glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials. Cosentino Claudia,Dicembrini Ilaria,Nreu Besmir,Mannucci Edoardo,Monami Matteo Diabetes research and clinical practice Sodium-glucose cotransporter 2 inhibitors (SGLT2i) decreased serum uric acid in type 2 diabetes. Hyperuricemia is associated with an increased risk of nephrolithiasis. The present meta-analysis, performed on trials with duration ≥52 weeks in comparison with placebo or active comparators, suggests no effects of SGLT-2i on the risk of nephrolithiasis. 10.1016/j.diabres.2019.107808
    Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and microvascular outcomes in patients with type 2 diabetes: systematic review and meta-analysis. Dorsey-Treviño E G,González-González J G,Alvarez-Villalobos N,González-Nava V,Contreras-Garza B M,Díaz González-Colmenero A,Rodríguez-Tamez G,Barrera-Flores F J,Farrell A M,Montori V M,Rodriguez-Gutierrez R Journal of endocrinological investigation PURPOSE:The effect of the sodium-glucose 2 (SGLT-2) inhibitors on microvascular complications remains uncertain. We performed a systematic review to determine the efficacy of the SGLT-2 inhibitors on microvascular outcomes in patients with type 2 diabetes. METHODS:A comprehensive search was performed using Ovid, MEDLINE, EMBASE, Web of Science, and Scopus from inception to May 2019. Randomized trials comparing SGLT-2 inhibitors with placebo or other medication for type 2 diabetes for ≥ 4 weeks were included. Diabetes-related microvascular complications such as nephropathy, retinopathy, neuropathy, and peripheral vascular disease were evaluated. A random-effect model using mean differences for continuous outcomes and risk ratio for dichotomous outcomes was used to synthesize data. PROSPERO (CRD 42017076460). RESULTS:A total of 40 RCTs with overall moderate quality of evidence were included. SGLT-2 inhibitors reduced the risk of renal-replacement therapy (0.65; 95% CI 0.54-0.79), renal death (0.57; 95% CI 0.49-0.65), and progression of albuminuria (0.69; 95% CI 0.66-0.73). Conversely, they appeared ineffective in maintaining eGFR (0.33; 95% CI - 0.74 to 1.41) or reducing serum creatinine (- 0.07; 95% CI - 0.26 to 0.11), whereas urine albumin-creatinine ratio (- 23.4; 95% CI - 44.6 to - 2.2) was reduced. Risk of amputation was non-significant (1.30; 95% CI 0.93-1.83). No available data were found regarding neuropathy and retinopathy to perform a quantitative analysis. CONCLUSION:SGLT-2 inhibitors may reduce the risk of renal patient-important outcomes but fail to improve surrogate outcomes. Apparently, no increased risk of amputations was observed with these medications. No data were available regarding other microvascular complications. 10.1007/s40618-019-01103-9
    Glycemic efficacy and safety of glucagon-like peptide-1 receptor agonist on top of sodium-glucose co-transporter-2 inhibitor treatment compared to sodium-glucose co-transporter-2 inhibitor alone: A systematic review and meta-analysis of randomized controlled trials. Patoulias Dimitrios,Stavropoulos Konstantinos,Imprialos Konstantinos,Katsimardou Alexandra,Kalogirou Maria-Styliani,Koutsampasopoulos Konstantinos,Zografou Ioanna,Papadopoulos Christodoulos,Karagiannis Asterios,Doumas Michael Diabetes research and clinical practice OBJECTIVE:Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now considered as key players in the treatment of type 2 diabetes mellitus (T2DM). The purpose of this meta-analysis was to provide precise effect estimates regarding the safety and efficacy of the addition of a GLP-1RA on top of SGLT-2i treatment. RESEARCH DESIGN AND METHODS:PubMed and CENTRAL, along with grey literature sources, were searched from their inception to May 2019 for randomized controlled trials (RCTs) with a duration ≥ 12 weeks, evaluating the safety and efficacy of addition of a GLP-1RA on a SGLT-2i compared to SGLT-2i alone in patients with T2DM. We also used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the credibility of our summary estimates. RESULTS:We identified three eligible RCTs, pooling data retrieved from 1,042 patients with T2DM in total. Administration of the maximum dose of a GLP-1RA on top of SGLT-2i treatment compared to SGLT-2i alone resulted in significant decrease in HbA1c by 0.91% (95% CI; -1.41 to -0.42) [GRADE: moderate], in body weight by 1.95 kg (95% CI; -3.83 to -0.07) [GRADE: moderate], in fasting plasma glucose by 1.53 mmol/L (95% CI; -2.17 to -0.88) [GRADE: moderate] and in systolic blood pressure levels by 3.64 mm Hg (95% CI -6.24 to -1.03). No significant effects on lipid profile and diastolic blood pressure were demonstrated. A significant increase in the risk for any hypoglycemia (RR: 2.62, 95% CI; 1.15-5.96, I = 33%) [GRADE: moderate] and for nausea (RR: 3.21, 95% CI; 1.36-7.54, I = 63%) [GRADE: moderate] and a non-significant increase in the risk for diarrhoea (RR: 1.64, 95% CI; 0.98-2.75, I = 0%) [GRADE: low] were documented. No other safety issues were identified. CONCLUSIONS:This meta-analysis suggests that a GLP-1RA/SGLT-2i combination, if tolerated, exerts significant beneficial effects on glycemic control and body weight loss, however increasing the risk for any hypoglycemia and gastrointestinal adverse events. 10.1016/j.diabres.2019.107927
    Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: A meta-analysis. Zou Cai-Yan,Liu Xue-Kui,Sang Yi-Quan,Wang Ben,Liang Jun Medicine BACKGROUND:Optimal glycemic control is required to restrain the increase of cardiovascular events in patients with type 2 diabetes. The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular events and mortality in those patients are not well established. This meta-analysis was conducted to assess the effects of SGLT2 inhibitors on cardiovascular events and mortality in patients with type 2 diabetes. METHODS:We conducted a systematic literature search of Medline, Embase and Cochrane Library and included randomized controlled trials (RCTs) of 3 different SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) that evaluated the effects on cardiovascular outcomes and mortality in the final meta-analysis. The intervention arm was defined either as SGLT2 inhibitor monotherapy or as SGLT2 inhibitor add-on to other non-SGLT2 inhibitor antidiabetic agents (ADAs). RESULTS:Forty-two trials with a total of 61,076 patients with type 2 diabetes were included in the meta-analysis. Compared with the control, SGLT2 inhibitor treatment was associated with a reduction in the incidence of major adverse cardiovascular events (MACEs) (OR = 0.86, 95% CI 0.80-0.93, P < .0001), myocardial infarction (OR = 0.86, 95% CI 0.79-0.94, P = .001), cardiovascular mortality (OR = 0.74, 95% CI 0.67-0.81, P < .0001) and all cause mortality (OR = 0.85, 95% CI 0.79-0.92, P < .0001). However, the risk of ischemic stroke was not reduced after SGLT2 inhibitor treatment in patients with type 2 diabetes (OR = 0.95, 95% CI 0.85-1.07, P = .42). CONCLUSION:These data suggest a decreased risk of harm with SGLT2 inhibitor as a class with respect to cardiovascular events and mortality. 10.1097/MD.0000000000018245
    Cardiovascular Outcomes With the Use of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes and Chronic Kidney Disease: An Updated Meta-Analysis of Randomized Controlled Trials. Malik Aaqib H,Yandrapalli Srikanth,Goldberg Michael,Jain Diwakar,Frishman William H,Aronow Wilbert S Cardiology in review Diabetes mellitus (DM) and chronic kidney disease (CKD) significantly increase the risk of cardiovascular morbidity and mortality. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a new class of hypoglycemic agents that have shown significant promise in the reduction of cardiovascular events. Current guideline recommendations do not support the use of these agents in patients with CKD stage 3 or higher. We performed a comprehensive meta-analysis to evaluate their cardiovascular effects in patients with type 2 DM and CKD stage 3 or higher. A comprehensive search was performed in PubMed, Cochrane central, and Embase. Software R was utilized to perform a meta-analysis via the generic inverse variance method. Additionally, we conducted a network meta-analysis to compare the relative efficacy and safety of each agent. Data from 7 randomized controlled trials and 6527 participants were available. In patients with type 2 DM and CKD, SGLT-2 inhibitor use resulted in a significant relative risk reduction of myocardial infarction (22%), heart failure hospitalization (39%), and major adverse cardiac events (20%) (all P-value < 0.05). There was also a trend towards a reduction in stroke and cardiovascular mortality. In a network meta-analysis, canagliflozin was the most effective in reducing myocardial infarction, stroke, and heart failure hospitalization. Empagliflozin performed better for the outcome of cardiovascular mortality, but the results failed to reach significance. In conclusion, SGLT-2 inhibitors significantly improve cardiovascular outcomes in patients with type 2 DM and CKD stage 3 or higher, providing a compelling reason for their use in this population subgroup. 10.1097/CRD.0000000000000265
    Efficacy of SGLT-2 inhibitors in older adults with diabetes: Systematic review with meta-analysis of cardiovascular outcome trials. Giugliano Dario,Longo Miriam,Maiorino Maria Ida,Bellastella Giuseppe,Chiodini Paolo,Solerte Sebastiano Bruno,Esposito Katherine Diabetes research and clinical practice AIMS:Sodium-glucose cotransporter-2 inhibitors (gliflozins) and statins are oral drugs that may have beneficial cardiovascular effects in patients with type 2 diabetes, especially in those with known cardiovascular disease. We planned a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) that evaluated the effect of gliflozins on MACE risk in patients with T2D stratified by age and by statin use. METHODS:The electronic search was carried out until 20 January 2020. RCTs were included if they were CVOTs performed in adults with T2D, compared add-on therapy with any gliflozin versus placebo, and had major cardiovascular events (MACE) as primary outcome. We limited the evaluation to MACE in order to minimize the statistical impact of post-hoc analyses. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. RESULTS:The hazard ratio for MACE was 0.95 (95% CI, 0.86-1.05) in people <65 years and 0.83 (95% CI, 0.71-0.96) for people ≥65 years, with no subgroup differences (P-value = 0.15), suggesting that the effect was consistent across age categories. The hazard ratio for MACE was 0.87 (95% CI, 0.81-0.94) in people taking a statin and 0.88 (95% CI, 0.77-1.01) for people not taking statin, with no subgroup differences (P-value = 0.90). CONCLUSIONS:The results are reassuring, as they confirm that the efficacy profile of gliflozins is unchanged by age, and may further enhance the CV protection offered by statin. 10.1016/j.diabres.2020.108114
    Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis. Tsapas Apostolos,Avgerinos Ioannis,Karagiannis Thomas,Malandris Konstantinos,Manolopoulos Apostolos,Andreadis Panagiotis,Liakos Aris,Matthews David R,Bekiari Eleni Annals of internal medicine BACKGROUND:Several pharmacologic options for type 2 diabetes are available. PURPOSE:To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. DATA SOURCES:Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. STUDY SELECTION:English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. DATA EXTRACTION:Pairs of reviewers extracted data and appraised risk of bias. DATA SYNTHESIS:453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. LIMITATION:Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. CONCLUSION:In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. PRIMARY FUNDING SOURCE:European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043). 10.7326/M20-0864
    Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals. Huang Chen-Yu,Lee Jen-Kuang Diabetes, obesity & metabolism AIM:To analyse large-scale cardiovascular outcome trials of sodium-glucose co-transporter-2 (SGLT-2) inhibitors to evaluate whether there are safety concerns with respect to major adverse limb events overall or among various high-risk subgroups of patients. METHODS:We performed a quantitative meta-analysis of randomized, placebo-controlled, cardiovascular outcome trials of SGLT-2 inhibitors in patients with type 2 diabetes. We searched the PubMed, Embase and Cochrane databases for trials published up until 30 June 2020. The efficacy outcomes analysed included amputations and were stratified by several subgroup variables, including age, duration of diabetes, glucose control, renal function, established peripheral artery disease and diabetes microvascular complications. This review was registered before completing the analysis. RESULTS:Among 383 records identified, six studies assessing the following three SGLT-2 inhibitors met our inclusion criteria: empagliflozin (EMPA-REG OUTCOME study), canagliflozin (CANVAS Program and CREDENCE study), dapagliflozin (DECLARE-TIMI 58 and DAPA-HF trials) and ertugliflozin (VERTIS CV study). Of a total of 51 713 participants, 858 required amputation operations. The event rates of amputation were 2.0% (535/26 778) and 1.3% (323/24 927) in the SGLT-2 inhibitor and control groups, respectively. The random effects model revealed that SGLT-2 inhibitors were not significantly associated with an increased risk of amputation with substantial heterogeneity (pooled risk ratio, 1.24; 95% confidence interval, 0.96 to 1.60; I = 67.5%). This neutral effect of SGLT-2 inhibitors was also consistent across different levels of subgroups, including subgroups with or without established peripheral artery disease (PAD). CONCLUSIONS:SGLT-2 inhibitors are not associated with increased risks of amputation operations even among various high-risk subgroups, including patients with PAD. The amputation events primarily arise from critical limb ischaemia and infection instead of acute limb ischaemia. A multi-centre study focused on major adverse limb events with a longer follow-up is needed to confirm these results and provide guidelines for clinical practice. 10.1111/dom.14159
    Heterogeneity of antidiabetic treatment effect on the risk of major adverse cardiovascular events in type 2 diabetes: a systematic review and meta-analysis. D'Andrea Elvira,Kesselheim Aaron S,Franklin Jessica M,Jung Emily H,Hey Spencer Phillips,Patorno Elisabetta Cardiovascular diabetology BACKGROUND:We explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE). METHODS:We investigated Medline and EMBASE through June 2019. We included randomized clinical trials reporting the effect of GLP-1 RA or SGLT-2i on MACE in subgroups of patients with type 2 diabetes, identified through key baseline factors: established cardiovascular disease; heart failure; chronic kidney disease; uncontrolled diabetes; duration of diabetes; hypertension; obesity; age; gender and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) from trials were meta-analyzed using random-effects models. RESULTS:Ten trials enrolling 89,790 patients were included in the analyses. Subgroup meta-analyses showed a 14% risk reduction of MACE in patients with established cardiovascular disease [GLP1-RA: HR, 0.86 (95% CI, 0.80-0.93); SGLT-2i: 0.86 (0.80-0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82-1.07); SGLT-2i: 1.00 (0.87-1.16)]. We observed a trend toward larger treatment benefits with SGLT-2i among patients with chronic kidney disease [0.82 (0.69-0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71-0.95); SGLT-2i: 0.84 (0.75-0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs. CONCLUSIONS:In this exploratory analysis, history of cardiovascular disease appeared to modify the treatment effect of SGLT2i or GLP1-RA on MACE. Chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers. 10.1186/s12933-020-01133-1
    Comparing the Efficacy and Safety of Glucagon-Like Peptide 1 Receptor Agonists with Sodium-Glucose Cotransporter 2 Inhibitors for Obese Type 2 Diabetes Patients Uncontrolled on Metformin: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. International journal of endocrinology INTRODUCTION:To conduct the first meta-analysis of randomized controlled trials (RCTs) comparing glucagon-like peptide 1 receptor agonists (GLP-1RAs) with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) for obese type 2 diabetes (T2D) patients uncontrolled on metformin. METHODS:We searched Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Ovid, and Web of Science from inception to May 14, 2020, without language restrictions for eligible RCTs. The primary outcome is the mean change from baseline in glycated haemoglobin (HbA1c). RESULTS:Totally, 3 RCTs enrolled 2066 patients were identified. Compared with SGLT-2is, treatment with GLP-1RAs achieved significant reduced HbA1c by 0.40% (95% CI: -0.54, -0.25; < 0.00001), fasting blood glucose (FBG) by 0.17 mmol/L (95% CI: -0.31, -0.04; =0.01), and postprandial blood glucose (PBG) by 0.32 mmol/L (95% CI: -0.49, -0.14; =0.0003) for obese T2D patients uncontrolled on metformin. The significant benefit of weight loss was seen in semaglutide (MD: -0.75; 95% CI: -1.18, -0.31; < 0.0007). No significant difference was detected between GLP-1RAs and SGLT-2is in overall adverse events (RR: 1.03; 95% CI: 0.98, 1.09; =0.76), but gastrointestinal events showed higher occurrence in GLP-1RAs groups compared with SGLT-2is (RR: 1.62; 95% CI: 1.37, 1.93; < 0.00001). Subgroup analyses revealed that follow-up time did not statistically influence glycemic control. CONCLUSION:GLP-1RAs are superior to SGLT-2is for obese T2D patients uncontrolled on metformin in glycemic control without an increase in adverse events except for a higher occurrence in gastrointestinal events. Future large longer-term follow-up clinical trials are needed to provide more evidence about the sustainable effects and safety of GLP-1RAs compared with SGLT-2is. 10.1155/2020/1626484
    Cardiovascular outcomes with glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes: A meta-analysis. Cardiology journal BACKGROUND:According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin. METHODS:Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported. RESULTS:Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.85-0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60-0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84-0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects. CONCLUSIONS:Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists. 10.5603/CJ.a2020.0140
    Does background metformin therapy influence the cardiovascular outcomes with SGLT-2 inhibitors in type 2 diabetes? Singh Awadhesh Kumar,Singh Ritu Diabetes research and clinical practice Metformin has been recommended as a first-line antidiabetic drug (ADD) for all patients with type 2 diabetes even in the presence of high cardiovascular (CV) risk by American Diabetes Association. In contrast, European Society of Cardiology recommends either a sodium-glucose co-transporter-2 inhibitors (SGLT-2i) or a glucagon-like peptide-1 receptor agonists as a first-line ADD, in presence of high CV risk. While this discordant recommendation has created a debate, we sought to find whether background metformin therapy influences the CV outcomes with SGLT-2i. We pooled the hazard ratio and 95% confidence interval of three-point composite major adverse cardiovascular events (3P-MACE) of 3 CV outcome trials (CVOTs) from the subgroup analysis based on outcomes with or without background metformin therapy. Subsequently, we conducted a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio, using a random-effects analysis. While this meta-analysis found a significant reduction in 3P-MACE with SGLT-2i without background metformin therapy (N = 7,233; HR 0.79; 95% CI, 0.69-0.90; p < 0.01; I = 0.0%), no significant reduction in 3P-MACE was observed with SGLT-2i in presence of background metformin therapy (N = 27,081; HR 0.94; 95% CI, 0.86-1.02; p = 0.13; I = 0.0%) with a significant P of 0.03 between the two groups. Similar finding was observed from the pooled results from 4 CVOTs. This may suggest that background metformin therapy may undermine the 3P-MACE benefit of SGLT-2i. However, no such interaction was observed in a recent meta-analysis of SGLT-2i, with or without background metformin therapy. Future research is warranted to understand the CV interaction of metformin with SGLT-2i. 10.1016/j.diabres.2020.108536
    Efficacy and Safety of SGLT-2 Inhibitors for Treatment of Diabetes Mellitus among Kidney Transplant Patients: A Systematic Review and Meta-Analysis. Chewcharat Api,Prasitlumkum Narut,Thongprayoon Charat,Bathini Tarun,Medaura Juan,Vallabhajosyula Saraschandra,Cheungpasitporn Wisit Medical sciences (Basel, Switzerland) BACKGROUND:The objective of this systematic review was to evaluate the efficacy and safety profiles of sodium-glucose co-transporter 2 (SGLT-2) inhibitors for treatment of diabetes mellitus (DM) among kidney transplant patients. METHODS:We conducted electronic searches in Medline, Embase, Scopus, and Cochrane databases from inception through April 2020 to identify studies that investigated the efficacy and safety of SGLT-2 inhibitors in kidney transplant patients with DM. Study results were pooled and analyzed utilizing random-effects model. RESULTS:Eight studies with 132 patients (baseline estimated glomerular filtration rate (eGFR) of 64.5 ± 19.9 mL/min/1.73m) treated with SGLT-2 inhibitors were included in our meta-analysis. SGLT-2 inhibitors demonstrated significantly lower hemoglobin A1c (HbA1c) (WMD = -0.56% [95%CI: -0.97, -0.16]; = 0.007) and body weight (WMD = -2.16 kg [95%CI: -3.08, -1.24]; < 0.001) at end of study compared to baseline level. There were no significant changes in eGFR, serum creatinine, urine protein creatinine ratio, and blood pressure. By subgroup analysis, empagliflozin demonstrated a significant reduction in body mass index (BMI) and body weight. Canagliflozin revealed a significant decrease in HbA1C and systolic blood pressure. In terms of safety profiles, fourteen patients had urinary tract infection. Only one had genital mycosis, one had acute kidney injury, and one had cellulitis. There were no reported cases of euglycemic ketoacidosis or acute rejection during the treatment. CONCLUSION:Among kidney transplant patients with excellent kidney function, SGLT-2 inhibitors for treatment of DM are effective in lowering HbA1C, reducing body weight, and preserving kidney function without reporting of serious adverse events, including euglycemic ketoacidosis and acute rejection. 10.3390/medsci8040047
    Microvascular Benefits of New Antidiabetic Agents: A Systematic Review and Network Meta-Analysis of Kidney Outcomes. Cha Ashley S,Chen Yilin,Fazioli Katherine,Rivara Matthew B,Devine Emily Beth The Journal of clinical endocrinology and metabolism CONTEXT:Diabetic kidney disease affects nearly one-third of US adults with prevalent type 2 diabetes mellitus (T2DM). The use of new antidiabetic medications in the prevention and treatment of diabetic kidney disease is a growing area of research interest. OBJECTIVE:We sought to characterize the risk of developing a composite kidney outcome among patients receiving a new antidiabetic medication of the SGLT-2i, GLP-1ra, and DPP-4i drug classes. METHODS:We conducted a systematic literature search in MEDLINE to identify randomized trials observing kidney safety endpoints associated with the use of new antidiabetic medications. Two independent reviewers selected the 7 eligible studies for analysis. Included studies were published between January 2013 and March 2020, conducted with adult participantss, published full-text in English, and observed composite kidney outcomes. A network meta-analysis was conducted within a Bayesian framework using a fixed-effects model with uninformative priors. RESULTS:A qualitative assessment of transitivity was conducted to ensure similar distribution of potential modifiers across studies. Included studies were generally comparable in mean age, glycated hemoglobin A1c (HbA1c), and mean duration of T2DM at baseline. MAIN CONCLUSIONS:Compared with placebo, dapagliflozin was associated with the greatest reduction in risk of developing the composite kidney outcome (hazard ratio 0.53; 95% credible interval, 0.43-0.66) followed by empagliflozin, canagliflozin, semaglutide, and liraglutide. Linagliptin did not show a significant reduction in risk of the outcome. LIMITATIONS:This analysis was limited by the scarcity of data for kidney safety endpoints in large, randomized clinical trials. Although the heterogeneity statistic was low, there are slight differences in study design and baseline demographic characteristics across trials. 10.1210/clinem/dgaa894
    Efficacy and safety of the newer oral hypoglycemic agents in patients with T2DM during Ramadan: A systematic review and meta-analysis. Gad Hoda,Hayat Tabraiz,Al-Muhannadi Hamad,Malik Balal Rasheed,Mussleman Paul,Malik Rayaz A Diabetes research and clinical practice AIMS:This systematic review and meta-analysis aims to evaluate the safety and efficacy of the newer glucose lowering treatments on glycemic control, weight, blood pressure and hypoglycemia in patients with T2DM during Ramadan. METHODS:A literature search was done in PubMed, Embase, and the Cochrane Library. Quality assessment was done using the ROBINS-I and Cochrane tools for risk of bias and analyses were performed using RevMan version 5.3. RESULTS:A total of 20 studies were included in the meta-analysis. Dipeptidyl peptidase-4 inhibitors (DPP-4i) led to a significant reduction in Hb (%) (SMD -0.25) and a non-significant decrease in weight (kg) (SMD -1.06) during Ramadan. Glucagon-like peptide (GLP-1) agonist therapy was associated with a significant decrease in Hb (%) (SMD -0.68) and a non-significant decrease in weight (kg) (SMD -2.57) and systolic blood pressure (SBP) (mmHg) (SMD -3.50) after Ramadan. Sodium-glucose co-transporter 2 inhibitor (SGLT-2i) therapy was associated with a significant decrease in Hb (%) (SMD -0.51) and a non-significant decrease in weight (kg) (SMD -1.41), SBP (SMD -1.10) and diastolic blood pressure (DBP) (mmHg) (SMD -2.08) after Ramadan. CONCLUSIONS:This systematic review and meta-analysis shows clinical benefits with the newer glucose lowering medications in patients with T2DM who fast during Ramadan. 10.1016/j.diabres.2020.108562
    Incretin based therapies and SGLT-2 inhibitors in kidney transplant recipients with diabetes: A systematic review and meta-analysis. Oikonomaki Dora,Dounousi Evangelia,Duni Anila,Roumeliotis Stefanos,Liakopoulos Vassilios Diabetes research and clinical practice AIMS:We aimed to conduct a systematic review and meta-analysis regarding the use of incretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists as well as sodium-glucose co-transporter-2 (SGLT2) inhibitorsin persons with posttransplantation diabetes mellitus (PTDM) so as to assess both their efficacy and safety. METHODS:We searched for publications on Kidney/Renal Transplantation and DPP-4 inhibitors, GLP-1-receptor agonists and SGLT-2 inhibitors and included every study using these antidiabetics. A p-value < 0.05 was considered statistical significant. RESULTS:Sixteen studies and 310 individuals with a mean age of 55.98 ± 8.81 years were included in the analysis. Participants received DPP-4 inhibitors in 8 studies, SGLT-2 inhibitors in 6 studies and GLP-1 receptor agonists in 2 studies, with a mean follow-up of 22.03 ± 14.95 weeks. Hemoglobin A1c (HbA1c) reduction was demonstrated in 10 studies (mean +/- standard deviation (MD) = - 0.38%, I = 45%). MD of HbA1c was -0.3741 and -0.4596 mg/dl for DPP-4 inhibitors and SGLT-2 inhibitors respectively. Nine studies demonstrated differences in fasting plasma glucose (FPG) (MD = - 25,76) and 5 studies in post-prandial glucose (PPG) (MD = - 6.61) before and following treatment. Most studies did not show adverse effects on the glomerular filtration rate (GFR) and hepatic function. CONCLUSIONS:DPP-4 inhibitors and SGLT2 inhibitors appear both efficacious and safe in renal transplant recipients. More high-quality studies are required to guide therapeutic choices for PTDM. 10.1016/j.diabres.2020.108604
    Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression. Musso Giovanni,Sircana Antonio,Saba Francesca,Cassader Maurizio,Gambino Roberto PLoS medicine BACKGROUND:Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death). METHODS AND FINDINGS:We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies. CONCLUSIONS:In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA. 10.1371/journal.pmed.1003461
    Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Mantovani Alessandro,Petracca Graziana,Csermely Alessandro,Beatrice Giorgia,Targher Giovanni Metabolites Recent randomized controlled trials (RCTs) tested the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors to specifically treat nonalcoholic fatty liver disease (NAFLD). We systematically searched three electronic databases (up to 31 October 2020) for identifying placebo-controlled or head-to-head RCTs that used SGLT-2 inhibitors for treatment of NAFLD. No published RCTs with paired liver biopsy data were available for the meta-analysis. Primary outcome measures were changes in serum liver enzyme levels and liver fat content on imaging techniques. Overall, we included a total of twelve RCTs testing the efficacy of dapagliflozin ( = six RCTs), empagliflozin ( = three RCTs), ipragliflozin ( = two RCTs) or canagliflozin ( = one RCT) to specifically treat NAFLD for a median period of 24 weeks with aggregate data on 850 middle-aged overweight or obese individuals with NAFLD (90% with type 2 diabetes). Compared to placebo/reference therapy, treatment with SGLT-2 inhibitors significantly decreased serum alanine aminotransferase (weighted mean differences (WMD): -10.0 IU/L, 95%CI -12.2 to -7.79 IU/L; = 10.5%) and gamma-glutamyltransferase levels (WMD: -14.49 IU/L, 95%CI -19.35 to -9.63 IU/L, = 38.7%), as well as the absolute percentage of liver fat content on magnetic resonance-based techniques (WMD: -2.05%, 95%CI -2.61 to -1.48%; = 0%). In conclusion, SGLT-2 inhibitors seem to be a promising treatment option for NAFLD. 10.3390/metabo11010022
    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. Yamada Takayuki,Wakabayashi Mako,Bhalla Abhinav,Chopra Nitin,Miyashita Hirotaka,Mikami Takahisa,Ueyama Hiroki,Fujisaki Tomohiro,Saigusa Yusuke,Yamaji Takahiro,Azushima Kengo,Urate Shingo,Suzuki Toru,Abe Eriko,Wakui Hiromichi,Tamura Kouichi Cardiovascular diabetology BACKGROUND:Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. METHODS:We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. RESULTS:Thirteen studies 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]). A sensitivity 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]). CONCLUSIONS: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 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not. 10.1186/s12933-020-01197-z
    Effect of background insulin therapy on cardiovascular outcomes with SGLT-2 inhibitors in type 2 diabetes: A meta-analysis of cardiovascular outcome trials. Singh Awadhesh Kumar,Singh Ritu Diabetes research and clinical practice Cardiovascular (CV) benefits of SGLT-2 inhibitors (SGLT-2i) have been consistent in type 2 diabetes mellitus (T2DM). To find whether SGLT-2i show similar CV effects with insulin therapy in T2DM, we conducted a trial-level meta-analysis of CV outcome trials. This meta-analysis found SGLT-2i exert CV benefit, irrespective of background insulin therapy. 10.1016/j.diabres.2021.108648
    Effect of sodium-dependent glucose transporter inhibitors on glycated hemoglobin A1c after 24 weeks in patients with diabetes mellitus: A systematic review and meta-analysis. Chen Mao-Bing,Wang Hua,Zheng Qi-Han,Xu Hua-Lan,Cui Wei-Yan Medicine BACKGROUND:To evaluate dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, and sotagliflozin according to their effect on the glycated hemoglobin A1c (HbA1c) level in patients with type 2 diabetes mellitus. METHODS:The Web of Science, PubMed, Cochrane Library, EMBASE, and Clinical Trials databases were electronically searched to collect randomized controlled trials of patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used to perform the meta-analysis and to create plots. RESULTS:Finally, 27 studies were selected and included in this study. The meta-analysis results showed that sodium-dependent glucose transporter (SGLT) inhibitors significantly reduced the HbA1c level in patients with type 2 diabetes mellitus. However, these results were highly heterogeneous, so we conducted a subgroup analysis. The results of the subgroup analysis suggested that by dividing populations into different subgroups, the heterogeneity of each group could be reduced. CONCLUSIONS:SGLT inhibitors had a good effect on the HbA1c level in patients with type 2 diabetes mellitus, but there might be differences in the efficacy of SGLT inhibitors in different populations. It is hoped that more studies will be conducted to evaluate the efficacy and safety of SGLT inhibitors in different populations. REGISTRATION NUMBER:CRD42020185025. 10.1097/MD.0000000000024101
    Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. Palmer Suetonia C,Tendal Britta,Mustafa Reem A,Vandvik Per Olav,Li Sheyu,Hao Qiukui,Tunnicliffe David,Ruospo Marinella,Natale Patrizia,Saglimbene Valeria,Nicolucci Antonio,Johnson David W,Tonelli Marcello,Rossi Maria Chiara,Badve Sunil V,Cho Yeoungjee,Nadeau-Fredette Annie-Claire,Burke Michael,Faruque Labib I,Lloyd Anita,Ahmad Nasreen,Liu Yuanchen,Tiv Sophanny,Millard Tanya,Gagliardi Lucia,Kolanu Nithin,Barmanray Rahul D,McMorrow Rita,Raygoza Cortez Ana Karina,White Heath,Chen Xiangyang,Zhou Xu,Liu Jiali,Rodríguez Andrea Flores,González-Colmenero Alejandro Díaz,Wang Yang,Li Ling,Sutanto Surya,Solis Ricardo Cesar,Díaz González-Colmenero Fernando,Rodriguez-Gutierrez René,Walsh Michael,Guyatt Gordon,Strippoli Giovanni F M BMJ (Clinical research ed.) OBJECTIVE:To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN:Network meta-analysis. DATA SOURCES:Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES:Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS:764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS:In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42019153180. 10.1136/bmj.m4573
    Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Singh Awadhesh Kumar,Singh Ritu Diabetes & metabolic syndrome BACKGROUND AND AIMS:We conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF. METHODS:A systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model. RESULTS:This meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69-0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78-0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62-0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF). CONCLUSIONS:SGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant P for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF. 10.1016/j.dsx.2021.01.006
    Sodium Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Hospitalization in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Zhang Ailing,Luo Xufei,Meng Haiyang,Kang Jian,Qin Guijun,Chen Yaolong,Zhang Xiaojian Frontiers in endocrinology Aim:To evaluate the impact of sodium glucose cotransporter 2 inhibitors (SGLT-2i) on risk of heart failure hospitalization in patients with type 2 diabetes. Methods:We searched the PubMed, Embase, The Cochrane Library, CNKI, Wanfang, CBM, and other web knowledge databases for data from randomized controlled trials. We performed statistical analyses by using review Manager (RevMan) 5.3 and STATA 12.0 for meta-analysis. Results:Eight randomized controlled trials that compared SGLT-2i placebo met our inclusion criteria and were included in the study. The final meta-analysis included a total of 55,763 type 2 diabetes patients. Compared with placebo, SGLT-2i reduced the risk of heart failure hospitalization (RR, 0.63; 95% CI, 0.53 to 0.74; < 0.00001), MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke) (RR, 0.92; 95% CI, 0.86 to 0.98; < 0.007), cardiovascular death (RR, 0.78; 95%CI, 0.62 to 0.99;  = 0.04) in type 2 diabetes patients. SGLT-2i could reduce the risk of death from any cause (RR, 0.77; 95% CI, 0.59 to 1.01; = 0.06) without statistical significance in type 2 diabetes patients. Conclusion:Compared with placebo, SGLT-2i may reduce the risk of heart failure hospitalization, MACE, and cardiovascular death. Therefore, SGLT-2i may be an ideal choice for type 2 diabetes mellitus patient with heart failure. These results will help inform practitioners, patients, and authorities making appropriate choices in hypoglycemic therapy clinical practice. 10.3389/fendo.2020.604250
    Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Gan Sushrima,Dawed Adem Y,Donnelly Louise A,Nair Anand T N,Palmer Colin N A,Mohan Viswanathan,Pearson Ewan R Diabetes care BACKGROUND:The pathophysiology of type 2 diabetes differs markedly by ethnicity. PURPOSE:A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs). DATA SOURCES:A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords. STUDY SELECTION:A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis. DATA EXTRACTION:Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study. DATA SYNTHESIS:Change in HbA was evaluated by computing mean differences and 95% CIs between treatment and placebo arms. LIMITATIONS:The study is based on summarized data and could not be separated based on East Asians and South Asians. CONCLUSIONS:The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA. 10.2337/dc19-2419
    Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes. Sinha Binayak,Datta Debasis,Ghosal Samit JGH open : an open access journal of gastroenterology and hepatology Background and Aim:Sodium glucose cotransporter 2 inhibitors (SGLT-2i), by way of their unique mode of action, present an attractive strategy for the treatment of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), which often coexist and may lead to severe complications. However, the evidence for treatment with SGLT-2i is limited to small heterogeneous studies. Therefore, this meta-analysis was conducted to deduce the effects of SGLT-2i in NAFLD with type 2 diabetes (T2D). Methods:A web-based search identified nine randomized controlled trials from the Cochrane Library, Embase, and PubMed for this meta-analysis. The Comprehensive Meta-Analysis Software version 3 was used to calculate the effect size. Result:The outcomes of interest were analyzed from a pooled population of 11 369 patients-7281 on SGLT-2i and 4088 in the control arm. SGLT-2i therapy produced a statistically significant improvement in alanine aminotransferase [standardised mean difference (SDM), -0.21, 95% confidence interval (CI), -0.32 to -0.10, < 0.01], aspartate aminotransferase (Standardised mean difference (SDM), -0.15, 95% CI, -0.24 to -0.07, < 0.01), and liver fat as measured by proton density fat fraction (SDM, -0.98, 95% CI, -1.53 to -0.44, < 0.01) in comparison to standard of care or placebo. In addition, there was a significant reduction in glycosylated hemoglobin (SDM, -0.37, 95% CI, -0.60 to -0.14, < 0.01) and weight (SDM, -0.58, 95% CI, -0.93 to -0.23, < 0.01) in the SGLT-2i arm. Conclusion:This meta-analysis provides a convincing signal that SGLT-2i have a salutary effect on NAFLD in type 2 diabetes (T2D), probably driven by an improvement of glycemia and body weight, which in turn attenuates hepatic inflammation and hepatic fat accumulation. 10.1002/jgh3.12473
    Effect of SGLT inhibitors on weight and lipid metabolism at 24 weeks of treatment in patients with diabetes mellitus: A systematic review and network meta-analysis. Chen Mao-Bing,Wang Hua,Cui Wei-Yan,Xu Hua-Lan,Zheng Qi-Han Medicine BACKGROUND:The goals of improving quality of life and increasing longevity are receiving growing amounts of attention. Body weight and lipid metabolism are closely related to various complications of diabetes. The aim of this study was to rank SGLT inhibitors according to their efficacy with regard to weight and evaluate the effect of SGLT inhibitors on lipid metabolism at 24 weeks of treatment. METHODS:The Web of Science, PubMed, Cochrane Library, Embase, and Clinical Trials databases were electronically searched to collect randomized controlled trials involving patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the selected studies and extracted the outcome indexes. ADDIS 1.16.5 and STATA 16 software were used to perform the network meta-analysis and draw the plots. RESULTS:Ultimately, 36 studies were selected and included in this study. We found that all SGLT inhibitors were effective at reducing weight; canagliflozin was the most effective. SGLT inhibitors and placebo were not associated with significantly different serum cholesterol levels. SGLT inhibitors lowered serum triglyceride levels and increased serum high-density and low-density lipoprotein cholesterol levels. SGLT inhibitors also reduced the level of alanine aminotransferase. CONCLUSIONS:SGLT inhibitors can bring about weight loss in patients with T2DM and can also improve lipid metabolism. Therefore, patients with hyperlipidemia who have been unsuccessful at losing weight should consider taking SGLT inhibitors. In addition, SGLT inhibitors are hepatoprotective and appear to be safe for patients with mild to moderate liver dysfunction. TRIAL REGISTRATION:CRD42020198516. 10.1097/MD.0000000000024593
    Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis. Li Chun-Xing,Liang Shuo,Gao Lingyan,Liu Hua PloS one BACKGROUND AND AIMS:Glucose lowering agents that reduce the risk of major adverse cardiovascular events (MACE) would be considered a major advance. The reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large-scale randomized controlled studies (RCTs) and systematic reviews of RCTs, but exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we analyzed the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM). METHODS:We did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was MACE and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region. RESULTS:Fourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF (OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. SGLT-2i significantly reduced the risk of severe hypoglycemia (OR, 0.78; 95% CI 0.69,0.90, P<0.001) and lower limb amputation (OR, 0.83; 95% CI 0.71,0.98, P<0.001), but it may increase the risk of diabetic ketoacidosis. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20-30)% or < 15%, (15-30)% or <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% or <70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3-4) years of follow-up except for BKA followed up for 1 year. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States. CONCLUSIONS:The predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i has robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin. SGLT-2i does not increase the risk of severe hypoglycemia and lower limb amputation. 10.1371/journal.pone.0244689
    Novel antidiabetic drugs and risk of cardiovascular events in patients without baseline metformin use: a meta-analysis. Masson Walter,Lavalle-Cobo Augusto,Lobo Martín,Masson Gerardo,Molinero Graciela European journal of preventive cardiology AIMS:To evaluate the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major cardiovascular events (MACE) in metformin-naïve patients with type 2 diabetes (T2D). METHODS AND RESULTS:A meta-analysis was performed of randomized controlled clinical trials of GLP-1RAs and SGLT-2 inhibitors on T2D populations, after searching the PubMed/MEDLINE, Embase, and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoint, explored in the subgroup of SGLT-2 inhibitors studies, was cardiovascular death or hospitalization for heart failure. A random-effects meta-analysis model was applied. Six eligible trials (three studies of SGLT-2 inhibitors and three trials of GLP-1RAs), including 13 049 patients, were identified and considered eligible for the analyses. The new antidiabetic drugs were associated with a significant reduction in MACE [odds ratio (OR): 0.80, 95% confidence interval: 0.70-0.93; I2: 53%]. The subgroup analysis showed the following findings: GLP-1RAs group, OR: 0.77 (95% confidence interval 0.67-0.88); SGLT-2 inhibitors, OR: 0.85 (95% confidence interval 0.63-1.15). SGLT-2 inhibitors were associated with a significant reduction in hospitalization for heart failure or cardiovascular mortality incidence (OR: 0.67, 95% confidence interval: 0.47-0.95; I2: 78%). CONCLUSION:In this meta-analysis, new antidiabetic drugs reduced the incidence of MACE in metformin-naïve T2D patients. The beneficial effect was especially observed in the GLP-1RAs subgroup. The use of SGLT-2 inhibitors was associated with a reduction in cardiovascular death or hospitalization for heart failure. These results support the fact that metformin would not be indispensable to obtain positive cardiovascular effects when new antidiabetic drugs are administered. 10.1093/eurjpc/zwaa074
    Efficacy and safety of glucose-lowering agents in patients with type 2 diabetes: A network meta-analysis of randomized, active comparator-controlled trials. Mannucci Edoardo,Naletto Lara,Vaccaro Gabriele,Silverii Antonio,Dicembrini Ilaria,Pintaudi Basilio,Monami Matteo Nutrition, metabolism, and cardiovascular diseases : NMCD AIM:Aim of the present network meta-analysis (NMA) is the comparison across glucose-lowering drugs (GLA) concerning their effects on glucose control, body weight, hypoglycemia, gastrointestinal adverse events, and quality of life. DATA SYNTHESIS:This NMA includes randomized clinical trials comparing different head-to-head comparison trials with EMA-approved GLA in type 2 diabetes, with a duration of ≥52 weeks. All drugs have to be administered at the maximal approved dose. Primary endpoints were HbA1c at 12, 52, and 104+ weeks. Secondary endpoints were body weight, quality of life, hypoglycemia, and gastrointestinal disorders. Indirect comparisons of different GLA were performed by NMA choosing metformin as reference. The standardized difference in means (SDM) and Mantel-Haenzel Odds Ratio [MH-OR] (using random-effect models) with 95% Confidence Intervals were calculated for categorical and continuous variables, respectively. We included 68 trials fulfilling all inclusion criteria. At 12 weeks, when considering indirect comparisons, insulin secretagogues (IS) were associated with a significantly greater reduction in comparison with metformin (SDM, -0.3 [-0.4;-0.2]%); a significantly lower efficacy was observed for pioglitazone. At 52 weeks, IS were no longer associated with a greater reduction of HbA1c; whereas a significant decrease in HbA1c was observed for GLP-1 RA (SDM, -0.2 [-0.1;-0.3]%). At 104+ weeks, only SGLT-2 inhibitors showed a significantly greater HbA1c reduction (SDM, -0.2 [-0.1;-0.3]%), whereas sulfonylureas and insulin showed a significantly lower efficacy (SDM, 0.1 [0.0; 0.2]%), and 0.4 [0.3; 0.5]%, respectively). CONCLUSIONS:The results of this meta-analysis should be considered together with evidence on long-term outcomes for selecting the most appropriate drugs for individual patients. 10.1016/j.numecd.2020.12.030
    Sodium-glucose co-transporter-2 inhibitors for the prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis. Giugliano Dario,Longo Miriam,Caruso Paola,Maiorino Maria Ida,Bellastella Giuseppe,Esposito Katherine Diabetes, obesity & metabolism A meta-analysis of cardiorenal outcomes of sodium-glucose co-transporter-2 inhibitors (SGLT-2is) available in Europe or the United States in patients with type 2 diabetes (T2D) is presented. An electronic search up to 6 January 2021 was conducted to determine eligible trials. A total of eight cardiorenal outcomes trials of SGLT-2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) were identified, with 65,587 patients. Data were analysed using a random effects model. Overall, SGLT-2is were associated with a 12% reduced risk of major adverse cardiovascular events (MACE; HR = 0.88; 95% CI, 0.83-0.93; Q statistic, p = .19), with no significant heterogeneity (p for interaction = .465) between subgroups of patients with or without cardiovascular disease (CVD). The risk of the composite renal outcome was significantly reduced by treatment with SGLT-2is (HR = 0.61, 95% CI, 0.54-0.70), with no significant heterogeneity of associations with outcome (I = 37%, p = .11), and no difference in the risk between patients with or without CVD (p for interaction = .665). SGLT-2is have moderate benefits on MACE and major benefits on the progression of diabetic kidney disease. 10.1111/dom.14374
    Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis. Diabetology international AIMS:COVID-19 is associated with diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS) and euglycaemic DKA (EDKA); however, evidence regarding parameters affecting outcome and mortality rates is scarce. METHODS:A systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January 2020 to 7 January 2021 to identify all studies describing clinical profile, outcome and mortality rates regarding DKA, HHS, DKA/HHS and EDKA cases in COVID-19 patients. The appropriate Joanna Briggs Institute tools were used for quality assessment; quality of evidence was approached using GRADE. Univariate and multivariate analyses were used to assess correlations between clinical characteristics and outcome based on case reports. Combined mortality rates (CMR) were estimated from data reported in case report series, cross-sectional studies, and meta-analyses. The protocol was submitted to PROSPERO (ID: 229356/230737). RESULTS:From 312 identified publications, 44 were qualitatively and quantitatively analyzed. Critical COVID-19 necessitating ICU ( = 3 × 10), DKA/HHS presence ( = 0.021), and AKI ( = 0.037) were independently correlated with death. Increased COVID-19 severity ( = 0.003), elevated lactates ( < 0.001), augmented anion gap ( < 0.001), and AKI ( = 0.002) were associated with DKA/HHS. SGLT-2i were linked with EDKA ( = 0.004) and negatively associated with AKI ( = 0.023). CMR was 27.1% (95% CI 11.2-46.9%) with considerable heterogeneity (  = 67%). CONCLUSION:Acute diabetes-related metabolic emergencies in COVID-19 patients lead to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Previous SGLT-2i treatment, though associated with EDKA, might preserve renal function in COVID-19 patients. SUPPLEMENTARY INFORMATION:The online version contains supplementary material available at 10.1007/s13340-021-00502-9. 10.1007/s13340-021-00502-9
    Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials. European journal of internal medicine BACKGROUND:To investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus. METHODS:Electronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM). RESULTS:A total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72-0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62-0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76-0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77-0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86-0.93). CONCLUSIONS:Compared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF. 10.1016/j.ejim.2021.03.020
    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. Zheng Caiyun,Lin Meimei,Chen Yan,Xu Haiting,Yan Lingqun,Dai Hengfen Cardiovascular diabetology 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; I = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79-0.92; P < 0.0001; I = 26%; HHF RR: 0.69; 95% CI 0.64-0.81; P < 0.00001; I = 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. 10.1186/s12933-021-01272-z
    The different hypoglycemic effects between East Asian and non-Asian type 2 diabetes patients when treated with SGLT-2 inhibitors as an add-on treatment for metformin: a systematic review and meta-analysis of randomized controlled trials. Li Xianzhi,Zhang Qianping,Zhou Xiaojun,Guo Siyi,Jiang Shan,Zhang Yuhan,Zhang Ruzhen,Dong Jianjun,Liao Lin Aging AIMS:To investigate the efficacy and safety of SGLT-2 inhibitors as an add-on treatment for metformin between Asian and non-Asian T2DM. METHODS:A systematic literature search of PubMed, EMBASE, and the Cochrane Library was performed through August 2020 with the following keywords: Sodium-Glucose Transporter 2 Inhibitors, Sodium Glucose Transporter 2 Inhibitors, SGLT2 inhibitor, SGLT-2 inhibitors, type 2 diabetes, and randomized controlled trials. Double-blinded RCTs comparing SGLT-2 inhibitors as an add-on treatment for metformin and metformin monotherapy in adults with type 2 diabetes were included. A random effects model was used to calculate overall effect sizes. RESULTS:5 RCTs with 1193 Asian patients and 7 RCTs with 2098 non-Asian patients were investigated. The improvement in HbA1c and fasting blood glucose in the Asian patients (WMD, -0.73%; 95% CI, -1.01% to -0.46%, < 0.01; WMD, -1.51; 95% CI, -1.81 to -1.21, < 0.01, respectively) were both significantly better than in the non-Asians (WMD, -0.45%; 95% CI, -0.62% to -0.29%, < 0.01; WMD, -1.03; 95% CI, -1.27 to -0.78, < 0.01, respectively). The effect of weight loss was similar in the non-Asian patients and Asian patients. There was little difference in the improvement of systolic blood pressure between them. The risk of serious adverse events was not significantly increased between the Asian and non-Asian patients. CONCLUSION:SGLT-2 inhibitors as an add-on treatment for metformin are more efficacious in East Asian T2DM patients than in non-Asian T2DM patients without an additional risk of severe adverse events. 10.18632/aging.202945
    Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients. Uneda Kazushi,Kawai Yuki,Yamada Takayuki,Kinguchi Sho,Azushima Kengo,Kanaoka Tomohiko,Toya Yoshiyuki,Wakui Hiromichi,Tamura Kouichi Scientific reports Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors. 10.1038/s41598-021-89620-7
    Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis. Tsapas Apostolos,Karagiannis Thomas,Kakotrichi Panagiota,Avgerinos Ioannis,Mantsiou Chrysanthi,Tousinas Georgios,Manolopoulos Apostolos,Liakos Aris,Malandris Konstantinos,Matthews David R,Bekiari Eleni Diabetes, obesity & metabolism AIM:To compare the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. METHODS:We searched Medline, Embase, the Cochrane Library, and grey literature sources until 29 September 2020 for randomized controlled trials of at least 24 weeks' duration assessing the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. We performed frequentist network meta-analyses and calculated weighted mean differences and 95% confidence intervals combining trial arms of different approved doses of a given intervention into a single group. We evaluated the confidence in pooled estimates using the CINeMA (Confidence In Network Meta-Analysis) framework. RESULTS:In total, 424 trials (276 336 patients) assessing 21 antidiabetic medications from nine drug classes were included. Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide, exenatide twice-daily, liraglutide, and the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. The same agents also conferred the greatest reductions in systolic blood pressure. Metformin had a modest effect in reducing body weight and systolic blood pressure. Diastolic blood pressure was reduced with the SGLT-2 inhibitors pioglitazone, exenatide twice-daily and semaglutide. In subgroup analyses of trials with over 52 weeks' duration, semaglutide and SGLT-2 inhibitors reduced both body weight and systolic blood pressure. CONCLUSIONS:Semaglutide and SGLT-2 inhibitors conferred reductions both in body weight and blood pressure that were sustainable for over 1 year of treatment. These agents may be preferable treatment options for patients with type 2 diabetes who are overweight/obese and/or hypertensive. 10.1111/dom.14451
    The effects of sodium glucose co-transporter (SGLT) 2 inhibitors on hematocrit levels: a systematic review and meta-analysis of randomized controlled trials. Wang Xiaonan,Fu Ran,Liu Hongtao,Ma Yinling,Qiu Xuejia,Dong Zhanjun Annals of palliative medicine BACKGROUND:Previous studies have suggested benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors including improving glycemic control, lower body weight, uric acid-lowering effect and decreasing blood pressure. The aim of this study was to evaluate the effects of SGLT2 inhibitors on hematocrit (Hct) levels in patients with type 2 diabetes mellitus. METHODS:Embase, CENTRAL, PubMed and other databases were searched from the establishment of the database through to July 2020. Randomized controlled trials (RCTs) involving patients with type 2 diabetes mellitus who were treated with SGLT2 inhibitors were analyzed using the random effects model. Stata 12.0 statistical software was used to estimate the weighted mean difference (WMD) and the 95% confidence intervals (CIs). RESULTS:A total of 40 RCTs were included, comprising 21,050 patients. SGLT2 inhibitors resulted in a significant increase in Hct levels compared to patients treated with a placebo (WMD 2.67%, 95% CI, 2.53 to 2.82; P<0.001). Treatment with 2.5, 5, and 10 mg of dapagliflozin significantly increased Hct levels (WMD 1.96%, 2.27%, and 2.47%, respectively; P<0.001). Administration of 100 and 300 mg of canagliflozin also resulted in a significant increase in Hct (WMD 2.91% and 2.94%, respectively; P<0.001). Similarly, empagliflozin, at concentrations of 10 and 25 mg, caused a significant increase in Hct (WMD 3.39% and 3.44%, respectively; P<0.001). However, treatment with ipragliflozin (12.5 and 50 mg) and ertugliflozin (5 and 15 mg) only resulted in a slight increase in patient Hct levels (WMD 1.26% and 1.98%, respectively for ipragliflozin, P>0.05; WMD 2.24% and 2.64%, respectively for ertugliflozin; P>0.05). DISCUSSION:SGLT2 inhibitors, as a class of drugs, increased Hct levels in patients with type 2 diabetes, and this increase was slightly more pronounced at higher doses compared to lower doses. TRIAL REGISTRATION:The protocol of this study has been submitted to the PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/), and the registration number is CRD42020200699. 10.21037/apm-21-1022
    Comparison of cardiovascular outcomes and cardiometabolic risk factors between patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors: a meta-analysis. European journal of preventive cardiology AIMS:Prevention of cardiovascular outcomes is a goal of the management of patients with type 2 diabetes mellitus patients as important as lowering blood glucose levels. Among the various glucose-lowering agents, the effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2Is) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) on cardiovascular outcomes have become the focus of recent researches. METHODS AND RESULTS:A systematic search was performed through several online database. All studies that compared the effects of SGLT-2Is and DPP-4Is on cardiovascular outcomes and cardiometabolic risk factors were reviewed. A total of 30 studies were included. Compared with DPP-4Is, SGLT-2Is treatment reduced the risk of stroke [risk ratio (RR) = 0.80; 95% confidence interval (CI), 0.76-0.84], myocardial infarction (RR = 0.85; 95% CI, 0.81-0.89), heart failure (RR = 0.58; 95% CI, 0.54-0.62), cardiovascular mortality (RR = 0.55; 95% CI, 0.51-0.60), and all-cause mortality (RR = 0.60; 95% CI, 0.57-0.63). In addition, SGLT-2Is presented favourable effects on hemoglobinA1c, fasting plasma glucose, systolic blood pressure, and diastolic blood pressure. The differences in blood lipids were also compared. CONCLUSION:Sodium-glucose cotransporter-2 inhibitors are superior to DPP-4Is in terms of cardiovascular outcomes. Sodium-glucose cotransporter-2 inhibitors bring more benefits with respect to the cardiometabolic risk factors. 10.1093/eurjpc/zwab099
    SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Shi Nanjing,Shi Yetan,Xu Jingsi,Si Yuexiu,Yang Tong,Zhang Mengting,Ng Derry Minyao,Li Xiangyuan,Xie Fei Frontiers in public health Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients. We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI). We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97-1.14, = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02-3.17, = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46-6.43, = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45-0.98, = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05-1.49, = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99-2.21, = 0.05). Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear. 10.3389/fpubh.2021.668368
    Effect of SGLT-2 Inhibitors on Non-alcoholic Fatty Liver Disease among Patients with Type 2 Diabetes Mellitus: Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials. Oman medical journal OBJECTIVES:Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) is a common problem associated with obesity and type 2 diabetes mellitus (T2DM). There have been anecdotal reports of the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) in improving liver function parameters in those with concomitant T2DM and NAFLD/NASH. We sought to systematically evaluate the evidence of SGLT2Is in improving liver function parameters in T2DM patients with NAFLD, considering the risks of random error based on trial sequential analysis (TSA). We also performed a meta-analysis based on a random-effects model. METHODS:A systematic literature search was performed using the Medline, Cochrane, and Embase databases from inception to 20 October 2018. Primary outcome for meta-analyses was the changes in hepatic enzyme levels (alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase). We also performed a meta-analysis on changes in insulin resistance, glycemic, and lipid parameters using SGLT2Is as a secondary objective. RESULTS:Eight eligible randomized controlled studies were eligible for analysis. Meta-analysis showed the efficacy of two SLT2Is, dapagliflozin, and canagliflozin in reducing these enzymes level. TSA showed that canagliflozin significantly reduced the gamma-glutamyl transpeptidase level by weighted mean difference (-5.474, 95% confidence interval (CI): -6.289??-4.659) compared to others comparators, and the evidence is conclusive. Dapagliflozin also had a statistically significant reduction in glycated hemoglobin, which is a parameter of glycemic control and homeostatic model assessment for insulin sensitivity (HOMA-IR), which is a parameter of insulin sensitivity by a weight mean difference, -0.732 (95% CI: -1.087??-0.378) and -0.804 (95% CI: -1.336??0.272), respectively. CONCLUSIONS:This study indicated that canagliflozin effectively improves liver function parameters among patients with diabetes, while dapagliflozin is more effective in improving glycemic indices and insulin sensitivity. 10.5001/omj.2021.62
    Sodium-glucose cotransporter-2 Inhibitors in Heart Failure: An Updated Systematic Review and Meta-analysis of 13 Randomized Clinical Trials Including 14,618 Patients With Heart Failure. Shrestha Dhan Bahadur,Budhathoki Pravash,Sedhai Yub Raj,Karki Parag,Gurung Suja,Raut Sumit,Damonte Juan Ignacio,Del Buono Marco Giuseppe,Mojadidi Mohammad Khalid,Elgendy Islam Y,Patel Toralben,Patel Nimesh K Journal of cardiovascular pharmacology ABSTRACT:Sodium-glucose cotransporter-2 (SGLT-2) inhibitors showed benefit in patients with heart failure. In this updated meta-analysis, we evaluate the therapeutic efficacy and safety of SGLT-2 inhibitors in patients with heart failure. Different electronic databases were searched to find relevant articles. RevMan 5.4 was used for pooling data using a random/fixed-effects model, complemented by several sensitivity and subgroup analyses. A total of 13 randomized clinical trials including 14,618 patients with heart failure were included in analysis among 6797 studies screened. The overall mortality rate was 12.45% in the SGLT-2 group and 14.67% in the placebo group with 18% lower odds of overall mortality [odds ratio (OR), 0.82; confidence interval (CI), 0.75-0.91] in the SGLT-2 group. Odds of cardiovascular mortality was 18% lower (OR, 0.82; CI, 0.74-0.92) in the SGLT-2 group. The odds of hospitalization for heart failure (HHF) was 38% lower during the study period (OR, 0.62; CI, 0.56-0.68) in the SGLT-2 group. In addition, a benefit was seen for composite outcome HHF or mortality and considering subgrouping based on diabetes status, gender, and age groups. Although genital infection was significantly higher in the SGLT-2 group, the occurrence of severe adverse events, hypoglycemia, urinary tract infection, bone fracture, volume depletion, and other renal events did not differ between the 2 groups. Thus, SGLT-2 inhibitors improved cardiovascular outcomes among patients with heart failure with no significant difference in adverse events. Clinical benefit was comparable in diabetic and nondiabetic individuals, males and females, people in younger and older age groups with underlying heart failure, and HF with reduced ejection fraction. 10.1097/FJC.0000000000001099
    SGLT-2 inhibitors reduce the risk of cerebrovascular/cardiovascular outcomes and mortality: A systematic review and meta-analysis of retrospective cohort studies. Mascolo Annamaria,Scavone Cristina,Scisciola Lucia,Chiodini Paolo,Capuano Annalisa,Paolisso Giuseppe Pharmacological research Despite Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been associated with a reduced risk of heart failure in patients with type 2 diabetes mellitus (T2DM), the effect observed for other cardiovascular (CV) and cerebrovascular outcomes differed among clinical trials. Different observational studies have investigated the effects of SGLT2 inhibitors on these outcomes and mortality. The present meta-analysis aimed to assess the effects of SGLT2 inhibitors on the risk of CV (major adverse CV event - MACE, non-fatal myocardial infarction, or hospitalization for heart failure) and cerebrovascular (stroke) outcomes. A systematic review was conducted in Pubmed from January 1, 2012 to November 31, 2020. Only retrospective cohort studies including as control group users of dipeptidyl peptidase-4 (DPP-4) inhibitors or non-SGLT2 inhibitors were retained and analysed separately. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Of the 158 references identified, 20 articles were selected for meta-analysis, of which 13 considered the comparison with DPP-4 inhibitors and 7 the comparison with non-SGLT2 inhibitors. The pooled intention-to-treat analysis showed a reduced risk of stroke with SGLT2 inhibitors compared to DPP-4 inhibitors (Hazard ratio HR, 0.89; 95%CI, 0.82-0.96; I = 25%; p = 0.25) and non-SGLT2 inhibitors (HR, 0.83; 95%CI, 0.77-0.91; I2 = 11%; p = 0.34). Finally, SGLT2 inhibitors were also associated with a reduced risk of CV outcomes and mortality in all comparisons. Our data support contemporary society recommendations to prioritise the use of SGLT2 inhibitors in patients with T2DM and at high risk for CV complications. 10.1016/j.phrs.2021.105836
    Sodium-Glucose Co-Transporter Inhibitors and Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pandey Arjun K,Okaj Iva,Kaur Hargun,Belley-Cote Emilie P,Wang Jia,Oraii Alireza,Benz Alexander P,Johnson Linda S B,Young Jack,Wong Jorge A,Verma Subodh,Conen David,Gerstein Hertzel,Healey Jeff S,McIntyre William F Journal of the American Heart Association Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66-0.86]; I=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57-0.85]; I=0%)-similar to the effect estimate for patients without AF, value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF. 10.1161/JAHA.121.022222
    Systematic Review of Cardiovascular Outcome Trials Using New Antidiabetic Agents in CKD Stratified by Estimated GFR. Kidney international reports INTRODUCTION:Cardiovascular benefits observed with new antidiabetic agents may not extend to chronic kidney disease (CKD) patients. This study performed a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) using new antidiabetic agents stratified by kidney function. METHODS:MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials were searched for eligible studies up to November 16, 2020. Data were stratified by the trial entry estimated glomerular filtration rate (eGFR) and albuminuria. Primary major cardiovascular event (MACE) outcomes were extracted, and a meta-analysis with a random effects model was performed to estimate overall risk ratios (RRs). RESULTS:Our search identified 16 studies for inclusion (glucagon-like peptide-1 [GLP-1] analogues,  = 6; dipeptidyl-peptidase 4 [DPP-4] inhibitors,  = 4; and sodium-glucose cotransporter-2 [SGLT-2] inhibitors,  = 6) with a combined total of 150,816 participants (28.2% with eGFR <60 ml/min per 1.73 m,  = 42,534). The RR for MACE with GLP-1 analogues with an eGFR ≥60 ml/min per 1.73 m was 0.87 (95% confidence interval [CI], 0.77-0.98;  = 0.02) and 0.90 (95% CI, 0.78-1.04;  = 0.14) with an eGFR <60 ml/min per 1.73 m. The RR for MACE with DPP-4 inhibitors with eGFR ≥60 ml/min per 1.73 m was 0.99 (95% CI, 0.92-1.07;  = 0.86) and 0.99 (95% CI, 0.91-1.08;  = 0.86) with an eGFR <60 ml/min per 1.73 m. The RR for MACE with SGLT-2 inhibitors with an eGFR ≥60 ml/min per 1.73 m was 1.01 (95% CI, 0.92-1.10;  = 0.87) and 0.85 (95% CI, 0.75-0.95;  = 0.005) with an eGFR <60 ml/min per 1.73 m. Most analyses had significant heterogeneity. Sufficient albuminuria data were unavailable to analyze empirically. CONCLUSION:Clear evidence for MACE prevention in diabetes patients with an eGFR <60 ml/min per 1.73 m currently exists for SGLT-2 inhibitors only. However, similar GLP-1 analogue effect sizes suggest a lack of sufficient power rather than a lack of effect. 10.1016/j.ekir.2021.06.029
    The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials. Lin Donna Shu-Han,Lee Jen-Kuang,Hung Chi-Sheng,Chen Wen-Jone Diabetologia AIMS/HYPOTHESIS:Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking. METHODS:We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed. RESULTS:A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control. CONCLUSIONS/INTERPRETATION:SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles. PROSPERO REGISTRATION NUMBER:CRD42020206600. 10.1007/s00125-021-05529-w
    Sodium-glucose co-transporter 2 inhibitors on weight change and cardiometabolic profiles in individuals with overweight or obesity and without diabetes: A meta-analysis. Wong John,Chan Kwan Yi,Lo Kenneth Obesity reviews : an official journal of the International Association for the Study of Obesity Several meta-analyses have been conducted to evaluate the weight loss effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes, whereas pooled analysis focusing on individuals without diabetes is lacking. The objective of this systematic review and meta-analysis is to evaluate the effect of SGLT-2 inhibitor monotherapy on weight change and cardiometabolic profiles. Multiple databases were searched for randomized controlled trials reporting weight change effect of SGLT-2 inhibitor treatment compared with placebo for more than 12 weeks among individuals with overweight or obesity and without diabetes. A total of eight randomized controlled trials with 750 subjects were identified. SGLT-2 monotherapy was associated with significant reduction in body weight of -2.32 kg, compared to -1.01 kg for placebo, giving a mean difference of -1.31 kg. Significant reductions in body mass index and fasting blood glucose were observed, but not for the changes in waist circumference, fat mass, blood pressure, and lipid profile compared with placebo. SGLT-2 inhibitor monotherapy for 12 weeks or more can result in modest weight loss among people with overweight or obesity and without diabetes. Depending on pre-existing comorbidities or risk factors, SGLT-2 inhibitors can be considered adjuncts in the treatment of obesity. 10.1111/obr.13336
    Glycemic Variability Impacted by SGLT2 Inhibitors and GLP 1 Agonists in Patients with Diabetes Mellitus: A Systematic Review and Meta-Analysis. Lee Heeyoung,Park Se-Eun,Kim Eun-Young Journal of clinical medicine To investigate the effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists on glycemic variability (GV), the mean amplitude of glucose excursion (MAGE), mean blood glucose (MBG) levels, and percentage of time maintaining euglycemia were evaluated. Randomized controlled trials evaluating the efficacy of SGLT-2 inhibitors and GLP-1 agonists for treating people with diabetes were selected through searches of PubMed, EMBASE, and other databases. Sixteen studies were finally analyzed. There were no differences in the reductions in MAGE after treatment with SGLT-2 inhibitors or GLP-1 agonists (standardized mean difference (SMD) = -0.59, 95% CI = -0.82 to -0.36 vs. SMD = -0.43, 95% CI = -0.51 to -0.35, respectively), and treatment with SGLT-2 inhibitors was associated with an increased reduction in MBG levels (SMD = -0.56, 95% CI = -0.65 to -0.48, < 0.00001). Monotherapy and add-on therapy with medications were correlated with MAGE and MBG level reductions. In conclusion, SGLT-2 inhibitors and GLP-1 agonists were associated with a reduction in GV and could be alternatives for treating people with diabetes. 10.3390/jcm10184078
    Effects of sodium-glucose cotransporter 2 inhibitors on serum uric acid in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis. Hu Xiaodong,Yang Yue,Hu Xiaona,Jia Xiaomeng,Liu Hongzhou,Wei Minjie,Lyu Zhaohui Diabetes, obesity & metabolism AIMS:The present study aims to determine the effects of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on the serum uric acid (SUA) levels of patients with type 2 diabetes mellitus (T2DM) in Asia. METHODS:PubMed, CENTRAL, Embase and Cochrane Library databases were searched for randomized controlled trials of SGLT-2 inhibitors in patients with T2DM up to 15 July 2021, without language or date restrictions. RESULTS:In total, 19 high-quality studies (4218 participants) were included in the present network meta-analysis. All of the included SGLT-2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ipragliflozin, luseogliflozin and tofogliflozin) significantly decreased SUA levels compared with those of the control [total standard mean difference -0.965, 95% CI (-1.029, -0.901), p = .000, I  = 98.7%] in patients with T2DM. Subgroup analysis and meta-regression showed that the combined analysis of different inhibitors might lead to heterogeneity of the results. Therefore, among the SGLT-2 inhibitors, the results of the subsequent network meta-analysis revealed that luseogliflozin and dapagliflozin ranked the highest in terms of lowering SUA levels among the SGLT-2 inhibitors. Moreover, the network meta-analysis declared that luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) led to a superior reduction in SUA in patients with T2DM. CONCLUSIONS:SGLT-2 inhibitors could significantly reduce SUA levels in patients with T2DM, particularly luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) possess the best effects. Therefore, SGLT-2 inhibitors look extremely promising as an antidiabetes treatment option in patients with T2DM with high SUA. 10.1111/dom.14570
    Sodium-glucose cotransporter 2 inhibitors in patients with heart failure: a systematic review and meta-analysis of randomized trials. European heart journal. Quality of care & clinical outcomes AIMS:Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have now been evaluated for the treatment of heart failure in several placebo-controlled randomized controlled trials (RCTs) across various ejection fraction ranges, but these trials were powered for composite outcomes rather than individual clinical endpoints. We therefore performed a meta-analysis to assess their safety and efficacy on all-cause mortality, cardiovascular mortality, and heart failure hospitalizations. METHODS AND RESULTS:We performed a prospectively registered random-effects meta-analysis of all RCTs comparing SGLT-2 inhibitors to placebo in patients with heart failure. The pre-specified primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, heart failure hospitalizations, and the composite of cardiovascular mortality or heart failure hospitalization. Four trials with 15 684 patients were eligible. The SGLT-2 inhibitor tested was empagliflozin in two trials, dapagliflozin in one trial, and sotagliflozin in one trial. The weighted-mean follow-up was 20.0 months. The hazard ratio (HR) for all-cause mortality was 0.91, 95% confidence interval (CI) 0.82-1.01, P = 0.071. There was a 12% reduction in cardiovascular mortality (HR 0.88, 95% CI 0.79 to 0.97, P = 0.012), and a 30% reduction in heart failure hospitalization (HR 0.70, 95% CI 0.64 to 0.77, P < 0.001). CONCLUSION:SGLT-2 inhibitors significantly reduced cardiovascular mortality and heart failure hospitalizations in patients with heart failure. The effect appears consistent across three drugs studied in four trials. SGLT-2 inhibitors should become standard care for patients with heart failure. 10.1093/ehjqcco/qcab072
    Association between novel Glucose-Lowering drugs and risk of Asthma: A network Meta-Analysis of cardiorenal outcome trials. Diabetes research and clinical practice AIMS:This network meta-analysis aimed to evaluate the asthma risk associated with dipeptidyl peptidase (DPP)-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter (SGLT) 2 inhibitors. METHODS:Electronic databases were systematically searched up to March 2021 to include placebo-controlled cardiovascular (or cardiorenal) outcome trials that reported the asthma incidents in patients taking DPP-4 inhibitors, GLP-1RAs, or SGLT2 inhibitors. A random-effects network meta-analysis was conducted to estimate their odds ratio (ORs) and 95% confidence intervals (CIs). RESULTS:Nineteen trials including 218 asthma cases among 159,705 patients were included. Compared with placebo, SGLT2 inhibitors (OR, 0.59; 95% CI, 0.38-0.93) were significantly associated with a decreased risk of asthma while both DPP-4 inhibitors and GLP-1RAs did not significantly affect asthma risk. SGLT2 inhibitors were significantly associated with a lower risk of asthma than DPP-4 inhibitors (OR, 0.38; 95% CI, 0.18-0.79). There was no association between GLP-1RAs and DPP-4 inhibitors and between SGLT2 inhibitors and GLP-1RAs in risk of asthma. CONCLUSIONS:SGLT2 inhibitors might protect against asthma while DPP-4 inhibitors and GLP-1RAs did not significantly affect the asthma incident. Given the underreporting of asthma in this study, further investigations using real-world data as well as mechanistic studies are warranted to confirm our results. 10.1016/j.diabres.2021.109080
    Effects of SGLT-2 inhibitors on health-related quality of life and exercise capacity in heart failure patients with reduced ejection fraction: A systematic review and meta-analysis. He Zhiyu,Yang Lin,Nie Yutong,Wang Yu,Wang Yangyang,Niu Xiaowei,Bai Ming,Yao Yali,Zhang Zheng International journal of cardiology OBJECTIVE:Improving health-related quality of life (HRQoL) and exercise capacity is an important goal of treatment in heart failure (HF). However, evidence for the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the improvement of HRQoL and exercise capacity seems to be conflicted. We performed a systematic review and meta-analysis to evaluate the effects of SGLT-2 inhibitors on HRQL and exercise capacity in patients with heart failure and reduced ejection fraction (HFrEF). METHODS:All studies (up to March 20, 2021) evaluating the effects of SGLT-2 inhibitors on HRQoL and exercise capacity in patients with HFrEF were initially searched from four electronic search engines: PubMed, Web of Science, Cochrane Library, and SinoMed. All statistical analyses were performed with RevMan 5.4. RESULTS:We included 9 articles describing 7 trials with 9428 patients. SGLT-2 inhibitors group exhibited significant improvement in HRQoL assessed by Kansas City Cardiomyopathy Questionnaires (KCCQ) (MD: 2.13, 95% CI: 1.11 to 3.14, p < 0.001) and the rate of KCCQ-overall summary score improvement≥5 points (RR 1.15, 95%CI 1.08 to 1.21, P < 0.001) compared with placebo. No significant difference was observed in exercise capacity assessed by 6-min walk test distance between SGLT-2 inhibitors and placebo (MD 24.45, 95%CI -22.82 to 71.72, P = 0.31). CONCLUSIONS:Our meta-analysis demonstrates that SGLT-2 inhibitors significantly improve HRQoL, and supports the concept that SGLT-2 inhibitors do not significantly improve exercise capacity in patients with HFrEF. Studies with larger sample sizes and longer follow-up duration are needed to determine whether the treatment with SGLT-2 inhibitors may improve exercise ability. PROSPERO:CRD42021248346. 10.1016/j.ijcard.2021.10.008
    Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression. Maiorino Maria Ida,Longo Miriam,Scappaticcio Lorenzo,Bellastella Giuseppe,Chiodini Paolo,Esposito Katherine,Giugliano Dario Cardiovascular diabetology BACKGROUND:Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. METHODS:An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS:The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta =  - 0.298, P = 0.007), with significant heterogeneity (I = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta =  - 0.531, R = 100%), without heterogeneity (I = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. CONCLUSIONS:The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use. 10.1186/s12933-021-01401-8
    Effects of Sodium/Glucose Cotransporter Inhibitors on Atrial Fibrillation and Stroke: A Meta-Analysis. Ong How Ting,Teo Yao Hao,Teo Yao Neng,Syn Nicholas Lx,Wee Caitlin Fern,Leong Shariel,Yip Alicia Swee Yan,See Ray Meng,Ting Adriel Zhi Hen,Chia Alys Zq,Cheong Alex Jia Yang,Tan Benjamin Yong-Qiang,Ho Jamie Sin-Ying,Yeo Leonard Leong-Litt,Leow Aloysius Sheng-Ting,Yeo Tiong-Cheng,Wong Raymond Cc,Chai Ping,Kojodjojo Pipin,Sia Ching-Hui Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association OBJECTIVES:Recent clinical trials have shown the potential of sodium glucose cotransporter (SGLT) 2 inhibitors to reduce the risk of atrial fibrillation but not stroke. We conducted a systematic review and meta-analysis to clarify if SGLT2 or combined SGLT1/2 inhibitors affect the risk of atrial fibrillation and stroke in patients regardless of diabetic status. MATERIALS AND METHODS:Four electronic databases were searched on 21st November 2020 for studies evaluating outcomes of stroke and atrial fibrillation with SGLT2 or combined SGLT1/2 inhibitors in both diabetic and non-diabetic patients. Both random and fixed effect, pair-wise meta-analysis models were used to summarize the results of the studies. RESULTS:A total of 13 placebo-controlled, randomized-controlled trials were included. Eight trials comprising 35,702 patients were included in the analysis of atrial fibrillation outcomes and eight trials comprising 47,910 patients were included in the analysis of stroke outcomes. Patients on SGLT inhibitors, particularly SGLT2 inhibitors, had lower odds of atrial fibrillation (Peto odds ratio [95% confidence interval] = 0.76 [0.63-0.92]) compared to placebo. This effect remained significant with a follow-up duration longer than 1 year, in studies utilizing dapagliflozin, patients with type 2 diabetes mellitus, and patients with cardiovascular disease. No difference was observed in the odds of atrial fibrillation in patients with baseline heart failure. No effect was seen on the risk of stroke in patients taking SGLT inhibitors. CONCLUSIONS:SGLT2 inhibitors significantly reduced the odds of atrial fibrillation in diabetic patients. However, SGLT inhibitors did not significantly affect the risk of stroke. 10.1016/j.jstrokecerebrovasdis.2021.106159