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1.
Comparative effectiveness of cardiovascular, renal and safety outcomes of second-line antidiabetic drugs use in people with type 2 diabetes: A systematic review and network meta-analysis of randomised controlled trials.
Sim, R, Chong, CW, Loganadan, NK, Fong, AYY, Navaravong, L, Hussein, Z, Khunti, K, Lee, SWH
Diabetic medicine : a journal of the British Diabetic Association. 2022;(3):e14780
Abstract
AIMS: To compare the cardiovascular, renal and safety outcomes of second-line glucose-lowering agents used in the management of people with type 2 diabetes. METHODS MEDLINE, EMBASE and CENTRAL were searched from inception to 13 July 2021 for randomised controlled trials comparing second-line glucose lowering therapies with placebo, standard care or one another. Primary outcomes included cardiovascular and renal outcomes. Secondary outcomes were non-cardiovascular adverse events. Risk ratios (RRs) and corresponding confidence intervals (CI) or credible intervals (CrI) were reported within pairwise and network meta-analysis. The quality of evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria. Number needed to treat (NNT) and number needed (NNH) to harm were calculated at 5 years using incidence rates and RRs. PROSPERO (CRD42020168322). RESULTS We included 38 trials from seven classes of glucose-lowering therapies. Both sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) showed moderate to high certainty in reducing risk of 3-point major adverse cardiovascular events, 3P-MACE (network estimates: SGLT2i [RR 0.90; 95% CrI 0.84-0.96; NNT, 59], GLP1RA [RR 0.88; 95% CrI 0.83-0.93; NNT, 50]), cardiovascular death, all-cause mortality, renal composite outcome and macroalbuminuria. SGLT2i also showed high certainty in reducing risk of hospitalization for heart failure (hHF), ESRD, acute kidney injury, doubling in serum creatinine and decline in eGFR. GLP1RA were associated with lower risk of stroke (high certainty) while glitazone use was associated with an increased risk of hHF (very low certainty). The risk of developing ESRD was lower with the use of sulphonylureas (low certainty). For adverse events, sulphonylureas and insulin were associated with increased hypoglycaemic events (very low to low certainty), while GLP1RA increased the risk of gastrointestinal side effects leading to treatment discontinuation (low certainty). DPP-4i increased risk of acute pancreatitis (low certainty). SGLT2i were associated with increased risk of genital infection, volume depletion (high certainty), amputation and ketoacidosis (moderate certainty). Risk of fracture was increased with the use of glitazones (moderate certainty). CONCLUSIONS SGLT2i and GLP1RA were associated with lower risk for different cardiorenal end points, when used as an adjunct to metformin in people with type 2 diabetes. Additionally, SGLT2i demonstrated benefits in reducing risk for surrogate end points in kidney disease progression. Safety outcomes differ among the available pharmacotherapies.
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2.
Regional variation of effects of new antidiabetic medications in cardiovascular outcome trials.
Cotter, G, Davison, BA, Edwards, C, Senger, S, Teerlink, JR, Zannad, F, Nielsen, OW, Metra, M, Mebazaa, A, Chioncel, O, et al
American heart journal. 2021;:73-80
Abstract
BACKGROUND In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. METHODS We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. RESULTS The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). CONCLUSION The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.
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3.
Efficacy and safety of the newer oral hypoglycemic agents in patients with T2DM during Ramadan: A systematic review and meta-analysis.
Gad, H, Hayat, T, Al-Muhannadi, H, Malik, BR, Mussleman, P, Malik, RA
Diabetes research and clinical practice. 2021;:108562
Abstract
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 HbA1c (%) (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 HbA1c (%) (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 HbA1c (%) (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.
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4.
Meta-analysis of trials in non-alcoholic fatty liver disease with therapeutic interventions for metabolic syndrome.
Albert, SG, Wood, EM
Diabetes & metabolic syndrome. 2021;(5):102232
Abstract
AIMS: Non-alcoholic fatty liver disease [NAFLD] is associated with metabolic syndrome [MS]. Current guidelines restrict therapy for NAFLD, other than weight loss, in early non-fibrotic disease. It was postulated that intervention with therapies for MS may improve liver fat content. METHODS A systematic evaluation of Cochrane and PubMed databases was performed for NAFLD or NASH if they were: 1) interventions for metabolic syndrome or diabetes mellitus 2) randomized controlled trials [RCT], with 3) primary outcomes of liver fat content [LFC] (by magnetic resonance spectroscopy [MRS] or liver biopsy (Nonalcoholic Fatty Liver Disease Activity Score [NAS]). RESULTS There were 30 RCT (in 24 publications) of 2409 subjects. LFC decreased with pioglitazone (MRS, -8.0 ± 1.0 %, p < 0.001), diet and exercise (-7.8 ± 1.7 %, p < 0.001) and omega-3 fatty acids (-6.0 ± 2.5 %, p = 0.02). Decreases in NAS scores were significant for pioglitazone (-1.4 ± 0.4 units, p < 0.001) and D&E (-1.0 ± 0.1 units, p < 0.001). Weight loss correlated with improvement in LFC (p < 0.001) and NAS (p < 0.001). Lowered serum triglycerides correlated with final LFC (p < 0.001) and NAS scores (p < 0.001). CONCLUSIONS Therapies of MS with weight loss, antiglycemic and triglyceride lowering medicines improved LFC and NAS scores. Further studies are necessary to demonstrate if these therapies would pre-emptively limit progression of disease.
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5.
Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis With More Than 500 000 Patient-years.
Cintra, RM, Nogueira, AC, Bonilha, I, Luchiari, BM, Coelho-Filho, OR, Coelho, OR, Schwartzmann, P, Muscellie, E, Nadruz, W, Carvalho, LSF, et al
The Journal of clinical endocrinology and metabolism. 2021;(10):3060-3067
Abstract
BACKGROUND Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. PURPOSE To examine the impact of antihyperglycemic drugs and their association on HHF. DATA SOURCES Forty randomized controlled trials (RCTs) reporting HHF. STUDY SELECTION Published RCTs were the data source. DATA EXTRACTION Incidence rates of HHF. DATA SYNTHESIS Random additive-effects network meta-analysis showed that metformin (P = 0.55), sulfonylureas (P = 0.51), glucagon-like peptide-1 receptor-agonist (P = 0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P = 0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is + DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P < 0.0001) and 0.70 (95% CI, 0.60-0.81; P < 0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P = 0.0004) and 1.49 (95% CI, 1.18-1.88; P = 0.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P = 0.009). LIMITATIONS There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. CONCLUSIONS The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.
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6.
The effects of myo-inositol vs. metformin on the ovarian function in the polycystic ovary syndrome: a systematic review and meta-analysis.
Azizi Kutenaei, M, Hosseini Teshnizi, S, Ghaemmaghami, P, Eini, F, Roozbeh, N
European review for medical and pharmacological sciences. 2021;(7):3105-3115
Abstract
OBJECTIVE Recent studies have revealed that myo-inositol could be more influential in patients with polycystic ovary syndrome (PCOS). This study was aimed to determine and compare the effects of myo-inositol and metformin on hormonal and metabolic profiles and fertility outcomes. MATERIALS AND METHODS A comprehensive search was carried out among the English-language databases, including PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science, and the articles published from April 2010 to February 2019 were tracked down. The fixed and random-effects meta-analysis was used to estimate the pooled effect size. The meta-analysis was performed in Stata Version 14.0. RESULTS Nine studies with 331 patients treated with metformin and 307 patients treated with myo-inositol groups were included in the analysis. The research groups did not diverge significantly in terms of the basic characteristics, such as age and Body Mass Index (BMI). In the myo-inositol group, the levels of Luteinizing Hormone (LH) [12.55% (95% I: 11.41-13.68%)], S. testosterone [44.38% (95% CI: 38.09-50.67%)] and prolactin [7.97% (95% CI: 6.58- 9.37%)] were significantly higher than those recorded, i.e., LH [7.97% (95% CI: 6.58- 9.37%)], S. testosterone [8.48% (95% CI: 3.14-13.83%)] and prolactin [7.14% (95% CI: 1.50-14.79%)] for the metformin group (p<0.001). CONCLUSIONS Due to the dearth of related research and the high heterogeneity of the Randomized Clinical Trials (RCTs) included in other studies, the present systematic review could not establish any differences between metformin and myo-inositol concerning the hormonal profile and the ovarian function. However, the findings indicated that myo-inositol could improve fertility outcomes by modulating hyperandrogenism. Randomized trials are required to understand the mechanistic actions of myo-inositol in comparison with those of metformin regarding oocyte and embryo quality, fertilization, pregnancy, and live birth rates.
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7.
Clinical Adverse Events Associated with Sodium-Glucose Cotransporter 2 Inhibitors: A Meta-Analysis Involving 10 Randomized Clinical Trials and 71 553 Individuals.
Lin, DS, Lee, JK, Chen, WJ
The Journal of clinical endocrinology and metabolism. 2021;(7):2133-2145
Abstract
CONTEXT SGLT2is are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined adverse events (AEs) associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. OBJECTIVE This meta-analysis aimed to investigate the occurrence of various AEs associated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) and to examine the level of risk of AEs in patients with different underlying diseases. METHODS We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library on January 31, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose vs low dose). RESULTS Our analysis included 10 eligible studies with a total of 71 553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% CI 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72-0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs 0.96, P = .066). CONCLUSION The use of SGLT2is is generally safe. SGLT2is may be associated with increased risks of genital infection but are protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2is lies in the identification of high-risk populations and close surveillance of patients after treatment.
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8.
Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis.
Lian, J, Fu, J
Frontiers in endocrinology. 2021;:615409
Abstract
OBJECTIVE To systematically evaluate the effects of pioglitazone in the treatment of patients with prediabetes or T2DM combined with NAFLD. METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and ClinicalTrials databases were searched until August 2020 for publications written in English. Two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded the strength of evidence. Our primary outcomes were the individual number of patients with improvement of at least 1 point in each of the histological parameters. Baseline characteristic data, such as BMI, weight, total body fat, fasting plasma glucose and fasting plasma insulin, and liver biological indicators, such as triglyceride level, HDL cholesterol level, plasma AST, and plasma ALT, were used as secondary outcomes. RESULTS A total of 4 studies were included. Compared with placebo, pioglitazone significantly improved steatosis grade, inflammation grade and ballooning grade, while in the fibrosis stage, there was no significant improvement in pioglitazone compared with placebo. In addition, pioglitazone can also improve blood glucose and liver function. CONCLUSION Pioglitazone can significantly improve the histological performance of the liver and insulin sensitivity. Additionally, it can significantly reduce fasting blood glucose, glycosylated hemoglobin, plasma AST, ALT and other liver biological indicators. Due to the lack of relevant randomized controlled trials and short intervention times, long-term studies are still needed to verify its efficacy and safety. SYSTEMATIC REVIEW REGISTRATION [PROSPERO], identifier [CRD42020212025].
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9.
The effects of Cuminum cyminum on glycemic parameters: A systematic review and meta-analysis of controlled clinical trials.
Tavakoli-Rouzbehani, OM, Faghfouri, AH, Anbari, M, Papi, S, Shojaei, FS, Ghaffari, M, Alizadeh, M
Journal of ethnopharmacology. 2021;:114510
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cuminum Cyminum (CC) is a traditional herbal medicine using as an antiseptic, anti-carcinogenic, anti-mutagenic, anti-cancer, anti-hypertensive, anti-inflammatory, and antioxidant. Recently hypoglycemic characteristics of CC have been indicated. AIM OF THE STUDY We intended to conduct a meta-analysis on the effect of CC supplementation on glycemic parameters in patients with different chronic diseases. MATERIALS AND METHODS PubMed, Embase, Web of Science, and Scopus were searched until May 2021. Random effect model was conducted to perform the meta-analysis. Source of heterogeneity was explored using the meta-regression and subgroup analyses. The Cochrane Collaboration's tool was used to assess the quality of studies. The GRADE approach was used to assess the quality of evidence. RESULTS Findings of eight studies showed that CC supplementation reduced FBS (SMD = -1.4 mg/dl; 95 % CI: -2.29, -0.51; P = 0.002), HbA1c (SMD = -1.71 %; 95 % CI: -3.24, -0.18; P = 0.028), and HOMA-β (SMD = 0.46; 95 % CI: -0.62, 1.55; P = 0.404) significantly. Also, CC increased QUICKI level (SMD = 0.89; 95 % CI: 0.37, 1.4; P = 0.001. However, no significant effect of CC was observed on insulin (SMD = -0.70 μIU/dl; 95 % CI: -1.84, 0.45; P = 0.234) and HOMA-IR (SMD = 0.46; 95 % CI: -0.62, 1.55; P = 0.404). CONCLUSION CC had an improving effect on FBS, HbA1C, HOMA-B, and QUICKI. The effect of CC on amending HOMA-IR was significant after sensitivity analysis. However, the insulin level was not changed significantly.
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10.
Predictive models for cardiovascular and kidney outcomes in patients with type 2 diabetes: systematic review and meta-analyses.
Buchan, TA, Malik, A, Chan, C, Chambers, J, Suk, Y, Zhu, JW, Ge, FZ, Huang, LM, Vargas, LA, Hao, Q, et al
Heart (British Cardiac Society). 2021;(24):1962-1973
Abstract
OBJECTIVE To inform a clinical practice guideline (BMJ Rapid Recommendations) considering sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists for treatment of adults with type 2 diabetes, we summarised the available evidence regarding the performance of validated risk models on cardiovascular and kidney outcomes in these patients. METHODS We systematically searched bibliographic databases in January 2020 to identify observational studies evaluating risk models for all-cause and cardiovascular mortality, heart failure (HF) hospitalisations, end-stage kidney disease (ESKD), myocardial infarction (MI) and ischaemic stroke in ambulatory adults with type 2 diabetes. Using a random effects model, we pooled discrimination measures for each model and outcome, separately, and descriptively summarised calibration plots, when available. We used the Prediction Model Risk of Bias Assessment Tool to assess risk of bias of each included study and the Grading of Recommendations, Assessment, Development, and Evaluation approach to evaluate our certainty in the evidence. RESULTS Of 22 589 publications identified, 15 observational studies reporting on seven risk models proved eligible. Among the seven models with >1 validation cohort, the Risk Equations for Complications of Type 2 Diabetes (RECODe) had the best calibration in primary studies and the highest pooled discrimination measures for the following outcomes: all-cause mortality (C-statistics 0.75, 95% CI 0.70 to 0.80; high certainty), cardiovascular mortality (0.79, 95% CI 0.75 to 0.84; low certainty), ESKD (0.73, 95% CI 0.52 to 0.94; low certainty), MI (0.72, 95% CI 0.69 to 0.74; moderate certainty) and stroke (0.71, 95% CI 0.68 to 0.74; moderate certainty). This model does not, however, predict risk of HF hospitalisations. CONCLUSION Of available risk models, RECODe proved to have satisfactory calibration in primary validation studies and acceptable discrimination superior to other models, though with high risk of bias in most primary studies. TRIAL REGISTRATION NUMBER CRD42020168351.