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Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.
De Buitléir, C, O' Connor, E, Satti, MM, Shaw, J, Liew, A
Diabetic medicine : a journal of the British Diabetic Association. 2021;(2):e14409
Abstract
AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.
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Use of dipeptidyl peptidase-4 inhibitors is associated with a lower risk of rheumatoid arthritis in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of cohort studies.
Charoenngam, N, Rittiphairoj, T, Ponvilawan, B, Ungprasert, P
Diabetes & metabolic syndrome. 2021;(1):249-255
Abstract
BACKGROUND AND AIMS Case reports have described occurrence of rheumatoid arthritis (RA) after initiation of Dipeptidyl Peptidase-4 Inhibitors (DPP4i), suggesting a possible adverse effect of the medications. However, the findings from subsequent cohort studies suggest the opposite as they indicate that T2DM patients who used DPP4i tended to have a lower risk of RA. We aimed to investigate the association between use of DPP4i and incident RA in patients with type 2 diabetes mellitus (T2DM) using systematic review and meta-analysis. METHODS Potentially eligible studies were identified from Medline and EMBASE databases from inception to May 2020 using search strategy that comprised of terms for "Dipeptidyl peptidase-4 inhibitor" and "Rheumatoid arthritis". Eligible study must be cohort study consisting of one cohort of patients with T2DM who were DPP4i users and another cohort of comparators with T2DM who did not receive DPP4i. Then, the study must report effect estimates with 95% confidence intervals (95% CIs) comparing incident RA between DPP4i users versus comparators. Point estimates with standard errors retrieved from each study were combined together using the generic inverse variance method. RESULTS A total of 709 articles were identified. After systematic review, four retrospective cohort studies met the eligibility criteria and were included into the meta-analysis. DPP4i users had a significantly lower risk of incident RA compared with comparators with the pooled hazard ratio of 0.72 (95% CI, 0.54-0.96; I2 75%). CONCLUSION This systematic review and meta-analysis found a significant association between DPP4i use and a lower risk of incident RA.
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Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients.
Rigato, M, Avogaro, A, Vigili de Kreutzenberg, S, Fadini, GP
The Journal of clinical endocrinology and metabolism. 2020;(7)
Abstract
OBJECTIVE The lipid profile represents a driver of cardiovascular risk in type 2 diabetes. The effect of chronic insulin therapy on cholesterol levels is unclear. We aim to evaluate the effect of basal insulin on lipid profile compared to other classes of antihyperglycemic agents in type 2 diabetic patients. DESIGN We performed a meta-analysis of randomized controlled trials reporting changes of lipid parameters in type 2 diabetic patients randomly assigned to basal insulin or other classes of anti-hyperglycemic agents. RESULTS The levels of total (TC) and low-density lipoprotein cholesterol (LDL-C) appeared to be significantly reduced by therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) in comparison to basal insulin (mean difference [MD] -3.80; 95% CI [-6.30 to -1.30] mg/dL, P < .001 and -4.17; 95% CI [-6.04 to -2.30] mg/dL, P < .0001), whereas no difference was detected between basal insulin and dipeptidyl peptidase-4 inhibitors (DPP4-I) or standard therapy (sulfonylurea ± metformin). Thiazolidinediones (TZD) produced a significant improvement in high-density lipoprotein cholesterol (HDL-C) (MD 3.55; 95% CI: 0.55 to 6.56 mg/dL, P = .02) but were associated with an increase in TC and LDL-C (MD 16.20; 95% CI: 9.09 to 23.31 mg/dL, P < .001 and 5.19: 95% CI: -3.00 to 13.39 mg/dL, P = .21). Basal insulin was superior to standard therapy in triglyceride reduction (MD 3.8; 95% CI: 0.99 to 6.63 mg/dL, P = .008). CONCLUSIONS GLP-1RA were superior to basal insulin in the control of TC and LDL-C. Basal insulin effectively reduced serum triglycerides. TZD led to improvement in HDL-C. DPP4-I and standard therapy did not have any significant effect on lipid levels.
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Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis.
Zilli, RW, Rached, CDA, Silva, FPD, Baena, RC
Revista da Associacao Medica Brasileira (1992). 2020;(4):458-465
Abstract
After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.
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DPP4 Inhibitors in the Management of Hospitalized Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Rabizadeh, S, Tavakoli Ardakani, MA, Mouodi, M, Bitaraf, M, Shab-Bidar, S, Esteghamati, A, Nakhjavani, M
Advances in therapy. 2020;(9):3660-3675
Abstract
INTRODUCTION We studied the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on glycemic control in non-critically ill patients admitted to hospital. METHODS We searched MEDLINE and EMBASE for published studies in English up to July 2019. We included randomized clinical trials (RCTs) that compared DPP4 inhibitors plus insulin supplementation versus basal-bolus insulin regimen in the management of hyperglycemia non-critically ill patients with type 2 diabetes admitted to hospital. Mean difference (MD), relative risk (RR), and 95% confidence intervals (CI) were generated to interpret the data. RESULTS Of 401 papers, four RCTs including 648 participants met inclusion criteria. There was no significant difference in mean daily blood glucose level between the two groups (MD 4.63; 95% CI = - 1.57, 10.83; p = 0.14) (I2 = 14%, p = 0.32). Total insulin dose per day was lower in patients receiving DPP4 inhibitors (MD - 14.27; CI = - 22.47, - 6.07; p = 0.001) (I2 = 92%, p = 0.001). Also, the number of insulin injection was significantly lower in patients receiving DPP4 inhibitors (MD - 0.79; CI = - 1.01, - 0.57; p = 0.001) (I2 = 0%, p = 0.68). The rate of hypoglycemia was not significantly different between the two groups (RR 0.60, CI = 0.34, 1.074; p = 0.08) (I2 = 37.3%, p = 0.18). Treatment failure was not significantly different between the two groups (RR 0.87, CI = 0.64, 4.8; p = 0.38) (I2 = 49%, p = 0.11). CONCLUSION The results indicate that using DPP4 inhibitors plus basal or supplemental insulin in hospitalized patients is non-inferior to a standard basal-bolus insulin regimen and leads to a lower amount of insulin use and a lower rate of insulin injection. Limitations of this study were heterogeneity of baseline characteristics of included patients, small sample size, short duration, and non-uniformly defined outcome assessment parameters in the included studies.
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Patient-centered Management of Type 2 Diabetes Mellitus Based on Specific Clinical Scenarios: Systematic Review, Meta-analysis and Trial Sequential Analysis.
Pinto, LC, Rados, DV, Remonti, LR, Viana, LV, Pulz, GT, Carpena, MP, Borges, RP, Marobin, R, Beretta, MV, Pedrollo, EF, et al
The Journal of clinical endocrinology and metabolism. 2020;(11)
Abstract
INTRODUCTION New antihyperglycemic medications have been proven to have cardiovascular (CV) and renal benefits in type 2 diabetes mellitus (T2DM); however, an evidence-based decision tree in specific clinical scenarios is lacking. MATERIALS AND METHODS Systematic review and meta-analysis of randomized controlled trials (RCTs), with trial sequential analysis (TSA). Randomized controlled trial inclusion criteria were patients with T2DM from 1 of these subgroups: elderly, obese, previous atherosclerotic CV disease (ASCVD), previous coronary heart disease (CHD), previous heart failure (HF), or previous chronic kidney disease (CKD). Randomized controlled trials describing those subgroups with at least 48 weeks of follow-up were included. Outcomes: 3-point major adverse cardiovascular events (MACE), CV death, hospitalization due to HF, and renal outcomes. We performed direct meta-analysis with the number of events in the intervention and control groups in each subset, and the relative risk of the events was calculated. RESULTS Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) were the only antihyperglycemic agents related to a reduction in CV events in different populations. For obese and elderly populations, GLP-1 RA were associated with benefits in 3-point MACE; for patients with ASCVD, both SGLT2i and GLP-1 RA had benefits in 3-point MACE, while for patients with CHD, only SGLT2i were beneficial. CONCLUSIONS SGLT2i and GLP-1 RA reduced CV events in selected populations: SGLT2i led to a reduction in events in patients with previous CHD, ASCVD, and HF. GLP-1 RA led to a reduction in CV events in patients with ASCVD, elderly patients, and patients with obesity. Trial sequential analysis shows that these findings are conclusive. This review opens a pathway towards evidence-based, personalized treatment of T2DM. REGISTRATION PROSPERO CRD42019132807.
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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, S, Dawed, AY, Donnelly, LA, Nair, ATN, Palmer, CNA, Mohan, V, Pearson, ER
Diabetes care. 2020;(8):1948-1957
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Abstract
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 HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study. DATA SYNTHESIS Change in HbA1c 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.
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Network Meta-Analysis of Novel Glucose-Lowering Drugs on Risk of Acute Kidney Injury.
Zhao, M, Sun, S, Huang, Z, Wang, T, Tang, H
Clinical journal of the American Society of Nephrology : CJASN. 2020;(1):70-78
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BACKGROUND AND OBJECTIVES Little is known about the comparative effects of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), or sodium glucose cotransporter-2 (SGLT2) inhibitors on risk of AKI. This study aimed to compare the effects of these three novel classes of glucose-lowering drugs on AKI risk in patients with or without type 2 diabetes, by network meta-analysis of event-driven cardiovascular or kidney outcome trials. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We systematically searched electronic databases up to September 2020, and included 20 event-driven cardiovascular or kidney outcome trials (18 trials included patients with type 2 diabetes only, and two trials included patients with or without type 2 diabetes). A network meta-analysis using a frequentist approach was performed to compare the effects of DPP-4 inhibitors, GLP-1RAs, or SGLT2 inhibitors on risk of AKI, and estimate the probability for each intervention as the safest one. The primary analysis included 18 trials with type 2 diabetes only, and a secondary analysis included 20 trials. RESULTS In the 18 trials with a total of 2051 AKI events (range: 1-300) among 156,690 patients with type 2 diabetes only, our network meta-analysis showed that SGLT2 inhibitors were associated with a lower risk of AKI compared with placebo (odds ratio, 0.76; 95% confidence interval, 0.66 to 0.88), whereas both DPP-4 inhibitors and GLP-1RAs had neutral effects on risk of AKI. Moreover, SGLT2 inhibitors were significantly associated with a lower risk in AKI than both GLP-1RAs (odds ratio, 0.79; 95% confidence interval, 0.65 to 0.97) and DPP-4 inhibitors (odds ratio, 0.68; 95% confidence interval, 0.54 to 0.86). SGLT2 inhibitors have the highest probability of being the safest intervention (84%). The results were similar in the secondary analysis. CONCLUSIONS Current evidence indicates that SGLT2 inhibitors have a lower risk of AKI than both DPP-4 inhibitors and GLP-1RAs.
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Comparison of Efficacy of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Co-Transporter 2 Inhibitors Between Japanese and Non-Japanese Patients: A Meta-Analysis.
Ito, Y, Ambe, K, Hayase, T, Kobayashi, M, Tohkin, M
Clinical and translational science. 2020;(3):498-508
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We explored efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose co-transporter 2 inhibitors (SGLT2is) between Japanese and non-Japanese patients with type 2 diabetes mellitus by conducting a systematic review and meta-analysis. A literature search of public databases before May 2017 identified 91 (DPP-4i) and 63 (SGLT2i) randomized placebo-controlled trials (> 12-week treatment). Multivariate meta-regression analysis identified baseline hemoglobin A1c (HbA1c) levels and placebo responses as covariates affecting efficacy of two agent classes independently of study region (Japanese/non-Japanese). When accounted for covariates, DPP-4i caused more pronounced HbA1c reduction in Japanese studies than in non-Japanese studies by 0.18% difference (P < 0.05) while causing no difference in fasting plasma glucose reduction between regions. On the other hand, when adjusted by baseline HbA1c levels and placebo responses, efficacy of SGLT2i were comparable between regions. The contrasting results for two agent classes indicate that drug efficacy is affected by different pathophysiology at its therapeutic action point.
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Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure.
Sinha, B, Ghosal, S
Diabetes research and clinical practice. 2019;:8-16
Abstract
AIM: To assess the effects DPP-4i; SGLT2-i & GLP1-RA on CV death, MI, stroke and hHF. This is probably the first meta-analysis to assess the effects of these drugs on MI and stroke in totality, including non-fatal & fatal MI and stroke. METHODS Scientific databases were searched for RCTs with pre-specified inclusion criteria and each end-point from the selected 13 studies was reported as an effect size (M H odds ratio) with a 95% confidence interval P value. RESULTS The pooled analysis of all the 5 available CVOT with DPP-4i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke, CV death and hHF. The pooled analysis of all the 5 available CVOTs with GLP1-RA resulted in a neutral effect on MI. However, there was a statistically significant 12% reduction in CV death (P = 0.01), 13% reduction in stroke (P = 0.02) and 11% reduction the combined end points of MI & Stroke (P = 0.001). The impact of GLP1-RA inhibitors on hHF was neutral. The pooled analysis of all the 3 available CVOTs with SGLT2-i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke and CV death. There was however a statistically significant 28% reduction in hHF (P < 0.001). CONCLUSION DPP-4i & SGLT-2i are neutral as far as all aspects of CV outcomes are concerned except for hHF which is significantly reduced by the latter. GLP1-RA as a class reduce risk of ASCVD showing a significant reduction in MI and stroke.