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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.
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The effect of glucagon-like peptide 1 and glucagon-like peptide 1 receptor agonists on energy expenditure: A systematic review and meta-analysis.
Maciel, MG, Beserra, BTS, Oliveira, FCB, Ribeiro, CM, Coelho, MS, Neves, FAR, Amato, AA
Diabetes research and clinical practice. 2018;:222-235
Abstract
AIM: We reviewed clinical trials addressing the effect of glucacon-like peptide 1 (GLP-1) or GLP-1 receptor agonists (GLP-1RA) on energy expenditure (EE) in adults. MATERIALS AND METHODS PubMed, Science Direct and Web of Science were searched for clinical trials investigating the effect of GLP-1 or GLP-1RA on EE in adults. RESULTS Ten trials (93 participants) assessed the effect of GLP-1 administration over 1 to 48 h and found no change in resting EE (REE). Two out of three trials (62 participants) reported a significant decrease in diet-induced thermogenesis (DIT) following GLP-1 administration. Ten trials with exenatide (10 μg bid, for 10-52 weeks) or liraglutide (0.6, 1.2, 1.8 or 3 mg, for 3 days-52 weeks), with a total of 282 participants, indicated a neutral effect of these GLP-1RA on REE, DIT or physical activity-induced EE. Importantly, the longest trial with GLP-1RA reported a significant increase in REE in response to treatment with both exenatide or liraglutide and most trials reported that GLP-1RA-induced weight loss was not accompanied by decreased REE. CONCLUSIONS This review indicates that GLP-1 has no short-term effect on REE but may decrease DIT. The GLP-1RA exenatide and liraglutide have a neutral effect on REE, although it is not possible to rule out an increase in REE following prolonged treatment.
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Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis.
Cai, X, Ji, L, Chen, Y, Yang, W, Zhou, L, Han, X, Zhang, S, Ji, L
Journal of diabetes investigation. 2017;(4):510-517
Abstract
AIMS/INTRODUCTION To evaluate the efficacy of weight changes from baseline of the sodium-glucose cotransporter 2 (SGLT2) inhibitors treatment and glucagon-like peptide-1 (GLP-1) analogs treatment after comparisons with a placebo in type 2 diabetes patients, and the associated factors. MATERIALS AND METHODS Studies were searched from when recording began, June 2004, until June 2015, and re-searched in July 2016, and placebo-controlled randomized trials in type 2 diabetes patients with a study length of ≥12 weeks were included. RESULTS A total of 97 randomized controlled trials were included. Compared with a placebo, treatment with SGLT2 inhibitors was associated with a significantly greater decrease in weight change from baseline (weighted mean differences -2.01 kg, 95% confidence interval -2.18 to -1.83 kg, P < 0.001). Compared with a placebo, changes with GLP -1 treatment were also associated with a comparable decrease in weight change from baseline (weighted mean differences -1.59 kg, 95% confidence interval -1.86 to -1.32 kg, P < 0.001). Meta-regression analysis showed that the baseline age, sex, baseline glycated hemoglobin, diabetes duration or baseline body mass index were not associated with the weight change from baseline in SGLT2 inhibitors or in GLP-1 treatment corrected by placebo. Comparisons of weight changes from baseline corrected by placebo between SGLT2 inhibitors and GLP-1 treatment showed that the difference was not significant (P > 0.05). CONCLUSIONS According to the present meta-analysis, treatment with SGLT2 inhibitors and treatment with GLP-1 analogs led to comparable weight changes from baseline, which are both with significance when compared with placebo treatment.
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Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: A meta-analysis.
Song, X, Jia, H, Jiang, Y, Wang, L, Zhang, Y, Mu, Y, Liu, Y
Scientific reports. 2015;:10202
Abstract
This study assessed the effect of GLP-1 based therapies on atherosclerotic markers in type 2 diabetes patients. 31 studies were selected to obtain data after multiple database searches and following inclusion and exclusion criteria. Age and BMI of the participants of longitudinal studies were 59.8 ± 8.3 years and 29.2 ± 5.7 kg/m(2) (Mean±SD). Average duration of GLP-1 based therapies was 20.5 weeks. Percent flow-mediated diameter (%FMD) did not change from baseline significantly but when compared to controls, %FMD increased non-significantly following GLP-1-based therapies (1.65 [-0.89, 4.18]; P = 0.2; REM) in longitudinal studies and increased significantly in cross sectional studies (2.58 [1.68, 3.53]; P < 0.00001). Intima media thickness decreased statistically non-significantly by the GLP-1 based therapies. GLP-1 based therapies led to statistically significant reductions in the serum levels of brain natriuretic peptide (-40.16 [-51.50, -28.81]; P < 0.0001; REM), high sensitivity c-reactive protein (-0.27 [-0.48, -0.07]; P = 0.009), plasminogen activator inhibitor-1 (-12.90 [-25.98, 0.18]; P=0.05), total cholesterol (-5.47 [-9.55, -1.39]; P = 0.009), LDL-cholesterol (-3.70 [-7.39, -0.00]; P = 0.05) and triglycerides (-16.44 [-25.64, -7.23]; P = 0.0005) when mean differences with 95% CI in the changes from baselines were meta-analyzed. In conclusion, GLP-1-based therapies appear to provide beneficial effects against atherosclerosis. More randomized data will be required to arrive at conclusive evidence.
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Acute exercise and hormones related to appetite regulation: a meta-analysis.
Schubert, MM, Sabapathy, S, Leveritt, M, Desbrow, B
Sports medicine (Auckland, N.Z.). 2014;(3):387-403
Abstract
BACKGROUND Understanding of the impact of an acute bout of exercise on hormones involved in appetite regulation may provide insight into some of the mechanisms that regulate energy balance. In resting conditions, acylated ghrelin is known to stimulate food intake, while hormones such as peptide YY (PYY), pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1) are known to suppress food intake. OBJECTIVE The objective of this review was to determine the magnitude of exercise effects on levels of gastrointestinal hormones related to appetite, using systematic review and meta-analysis. Additionally, factors such as the exercise intensity, duration and mode, in addition to participant characteristics, were examined to determine their influence on these hormones. DATA SOURCES Major databases (PubMed, Scopus, Google Scholar, Science Direct, Academic Search Premier and EBSCOHost) were searched, through February 2013, for original studies, abstracts, theses and dissertations that examined responses of appetite hormones to acute exercise. STUDY SELECTION Studies were included if they evaluated appetite hormone responses during and in the hours after an acute bout of exercise and reported area under the concentration-time curve (AUC) values for more than three datapoints. Studies reporting mean or pre/post-values only were excluded. STUDY APPRAISAL AND SYNTHESIS Initially, 75 studies were identified. After evaluation of study quality and validity, using the Physiotherapy Evidence Database scale, data from 20 studies (28 trials) involving 241 participants (77.6 % men) had their data extracted for inclusion in the meta-analyses. A random-effects meta-analysis was conducted for acylated ghrelin (n = 18 studies, 25 trials) and PYY (n = 8 studies, 14 trials), with sub-group analyses and meta-regressions being conducted for moderator variables. Because the number of studies was limited, fixed-effects meta-analyses were performed on PP data (n = 4 studies, 5 trials) and GLP-1 data (n = 5 studies, 8 trials). RESULTS The results of the meta-analyses indicated that exercise had small to moderate effects on appetite hormone levels, suppressing acylated ghrelin (effect size [ES] Cohen's d value -0.20, 95 % confidence interval [CI] -0.373 to -0.027; median decrease 16.5 %) and increasing PYY (ES 0.24, 95 % CI 0.007 to 0.475; median increase 8.9 %), GLP-1 (ES 0.275, 95 % CI -0.031 to 0.581; median increase 13 %), and PP (ES 0.50, 95 % CI 0.11 to 0.89; median increase 15 %). No significant heterogeneity was detected in any meta-analysis (using Cochrane's Q and I (2)); however, publication biases were detected for all analyses. No moderator variables were observed to moderate the variability among the studies assessing acylated ghrelin and PYY. LIMITATIONS The majority of the present literature is acute in nature; therefore, longer-term alterations in appetite hormone concentrations and their influence on food and beverage intake are unknown. Furthermore, our review was limited to English-language studies and studies reporting AUC data. CONCLUSIONS An acute bout of exercise may influence appetite by suppressing levels of acylated ghrelin while simultaneously increasing levels of PYY, GLP-1 and PP, which may contribute to alterations in food and drink intake after acute exercise. Further longitudinal studies and exploration into mechanisms of action are required in order to determine the precise role these hormones play in long-term appetite responses to an exercise intervention.
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The effect of a dual combination of noninsulin antidiabetic drugs on lipids: a systematic review and network meta-analysis.
Dai, X, Wang, H, Jing, Z, Fu, P
Current medical research and opinion. 2014;(9):1777-86
Abstract
OBJECTIVE As an ever widening array of anti-hyperglycemic agents are now available, the effect of these drugs on lipids is increasingly complex and controversial. The present meta-analysis was designed to clarify the effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids in type 2 diabetes. METHODS Randomized controlled trials comparing different dual combinations of antidiabetic drugs were identified by searching PubMed, Cochrane Library, and Embase. Study selection, data abstraction and quality assessment were carried out by two reviewers independently. Change in low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride and total cholesterol were pooled by both traditional meta-analysis and network meta-analysis. RESULTS Eighteen studies with a total of 10,222 patients were included. Network meta-analysis suggested that metformin + dipeptidyl peptidase-4 inhibitors (DPP-4) (LDL cholesterol: -0.19 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.73 mmol/L; total cholesterol: -0.4 mmol/L) and metformin + glucagon-like peptide-1 (GLP-1) agonist (LDL cholesterol: -0.3 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.64 mmol/L; total cholesterol: -0.5 mmol/L) were associated with relatively larger beneficial effects on the lipid profile among all combinations. Compared with metformin + thiazolidinedione, metformin + GLP-1 agonist (mean difference: -0.38; 95% confidence interval [CI]: -0.66 to -0.10) significantly decreased LDL cholesterol. Metformin + thiazolidinedione showed a larger increase than metformin + sulfonylurea in HDL cholesterol (mean difference: 0.1; 95% CI: 0.01 to 0.21). CONCLUSIONS The effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids is moderate to small, with metformin + DPP-4 inhibitor and metformin + GLP-1 agonist showing consistent beneficial effects on LDL cholesterol, HDL cholesterol, triglycerides and total cholesterol. Future trials are needed to confirm these findings.
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Glucagon-like peptide analogues for type 2 diabetes mellitus.
Shyangdan, DS, Royle, P, Clar, C, Sharma, P, Waugh, N, Snaith, A
The Cochrane database of systematic reviews. 2011;(10):CD006423
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Abstract
BACKGROUND Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety. OBJECTIVES To assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus. SEARCH STRATEGY Studies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials. SELECTION CRITERIA Studies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes. DATA COLLECTION AND ANALYSIS Data extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model). MAIN RESULTS Seventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 μg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 μg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.None of the studies was long enough to assess long-term positive or negative effects. AUTHORS' CONCLUSIONS GLP-1 agonists are effective in improving glycaemic control.