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1.
Impact of glucagon-like peptide 1 receptor agonists and sodium-glucose transport protein 2 inhibitors on blood pressure and lipid profile.
Muzurović, E, Mikhailidis, DP
Expert opinion on pharmacotherapy. 2020;(17):2125-2135
Abstract
INTRODUCTION Type 2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular (CV) disease (CVD). Optimal anti-hyperglycemic agents should include control of multiple CV risk factors (RF) to improve macrovascular and microvascular complications, as well as glycemia. AREAS COVERED In this narrative review, the authors focus on the effects of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on blood pressure (BP) and the lipid profile, two well-established CV RF. EXPERT OPINION Results from recent CV outcome trials (CVOTs), showed the impact of GLP-1 RA and SGLT2i on BP and lipid levels. These classes of medication can alter cardiac function by affecting the process of atherosclerosis and/or hemodynamic status. The results of published GLP1-RA and SGLT2i CVOTs have shown multifactorial benefits; in addition to the main effects on glycemia and body weight (BW), there are also positive but moderate effects on BP and lipid levels. Full advantage of the pleiotropic benefit of these agents should be taken to prevent CV events.
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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, E, Kesselheim, AS, Franklin, JM, Jung, EH, Hey, SP, Patorno, E
Cardiovascular diabetology. 2020;(1):154
Abstract
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.
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Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: A systematic review and meta-analysis of cardio-vascular outcome trials.
Singh, AK, Singh, R
Diabetes & metabolic syndrome. 2020;(3):181-187
Abstract
BACKGROUND AND AIMS Type 2 diabetes confers a differential risk of cardiovascular (CV) disease according to the gender. Whether newly approved anti-diabetic drugs like sodium-glucose co-transport-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) that have shown a significant reduction in the CV end-points in CV outcome trials (CVOTs) also have a differential impact gender-wise, is still not clearly known. METHODS We systematically searched the medical database up to December 31, 2019 and retrieved all the dedicated CVOTs conducted with SGLT-2Is and GLP-1RAs that explicitly reported the outcome of major adverse cardiac events (MACE). Subsequently, we pooled the hazard ratio (HR) of MACE in both sexes separately and meta-analyzed the result gender-wise. RESULTS The meta-analysis of three CVOTs conducted with SGLT-2Is (N = 34,322), demonstrated a significant reduction in MACE in men but not in women (Men - HR, 0.90; 95% CI, 0.83 to 0.97; P = 0.006; Women - HR, 0.88; 95% CI, 0.77 to 1.00; P = 0.06) compared to placebo. The meta-analysis of seven CVOTs conducted with GLP-1RAs (N = 56,004) demonstrated a significant reduction in MACE in both sex (Men - HR, 0.88; 95% CI, 0.82 to 0.93; P < 0.0001; Women - HR, 0.88; 95% CI, 0.79 to 0.99; P = 0.03), against the placebo. CONCLUSIONS The reduction in MACE with SGLT-2Is appears to be significantly less in women with diabetes vs men, while GLP-1RAs confers a similar reduction in MACE, irrespective of the gender. Whether these results are related to inadequate statistical power (underrepresentation of women) in CVOT, or it reflects a true gender difference, still remains to be established.
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Glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors as add-on therapy for patients with type 2 diabetes? A systematic review and meta-analysis of surrogate metabolic endpoints.
Patoulias, D, Katsimardou, A, Kalogirou, MS, Zografou, I, Toumpourleka, M, Imprialos, K, Stavropoulos, K, Stergiou, I, Papadopoulos, C, Doumas, M
Diabetes & metabolism. 2020;(4):272-279
Abstract
OBJECTIVE As sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are second-line treatment options in type 2 diabetes mellitus (T2DM), our study sought to provide precise effect estimates regarding the role of GLP-1RAs vs SGLT-2is as add-on treatments in patients uncontrolled by metformin monotherapy. RESEARCH DESIGN AND METHODS PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and 'grey literature' were searched from their inception up to December 2019 for randomized controlled trials (RCTs) with durations≥12weeks to evaluate the safety and efficacy of adding a GLP-1RA vs an SGLT-2i in patients with T2DM. RESULTS Three eligible RCTs were identified. Administration of GLP-1RAs vs SGLT-2is resulted in significant decreases in HbA1c with no significant impact on either body weight or fasting plasma glucose. GLP-1RA treatment led to a significant increase in odds for achieving an HbA1c<7% compared with SGLT-2is, whereas no difference was detected in body weight reductions of>5%. Significantly greater risk for any hypoglycaemia, nausea and diarrhoea, and lower risk for genital infections, was also observed with GLP-1RAs, while no differences regarding severe hypoglycaemia, treatment discontinuation and impact on blood pressure levels were identified. No other major safety issues arose. CONCLUSION Our meta-analysis suggests that GLP-1RAs provide better glycaemic effects than SGLT-2is in patients with T2DM uncontrolled by metformin, albeit while increasing risk for hypoglycaemia and gastrointestinal adverse events.
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Trend 2010-2018 in the clinical use of GLP-1 receptor agonists for the treatment of type 2 diabetes in routine clinical practice: an observational study from Northeast Italy.
Fadini, GP, Frison, V, Rigato, M, Morieri, ML, Simioni, N, Tadiotto, F, D'Ambrosio, M, Paccagnella, A, Lapolla, A, Avogaro, A
Acta diabetologica. 2020;(3):367-375
Abstract
AIMS: Several GLP-1 receptor agonists (GLP-1RA) have become available for the treatment of type 2 diabetes (T2D), and evidence on their beneficial effects has evolved. We evaluated how the clinical phenotype of patients initiating GLP-1RA changed from 2010 to 2018. METHODS This was a retrospective study conducted at six diabetes outpatient clinics in Northeast Italy. We collected data of T2D patients who initiated new GLP-1RA between 2010 and 2018. We recorded baseline characteristics, including demographics, anthropometrics, cardiovascular risk factors, glucose control, lipid profile, liver enzymes, renal function and concomitant medications. We recorded updated HbA1c and body weight at follow-up. RESULTS There were 83,116 T2D patients from a general population of ~ 1,380,000 inhabitants. Among 6167 cases of GLP-1RA initiation, 5408 were analyzed after excluding intra-class switchers. Prescription of GLP-1RA increased exponentially, and the change in the type of GLP-1RA reflected waves of their entering the market. From 2010 to 2018, there were significant increases in baseline age, diabetes duration and prevalence of male sex, of cardiovascular disease and of insulin users. Blood pressure and cholesterol levels decreased concomitantly with increasing use of medications for the control of cardiovascular risk. Baseline average HbA1c (8.3% [67 mmol/mol]) and BMI (34 kg/m2) and their improvement after GLP-1RA initiation did not change over time. CONCLUSIONS Despite the early positioning of GLP-1RA in T2D treatment algorithms, GLP-1RA have been prescribed in patients with progressively more advanced disease stage and especially in the presence of cardiovascular disease. Optimization of GLP-1RA use in routine clinical practice is still needed.
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Effects of Sodium-Glucose Cotransporter Inhibitor/Glucagon-Like Peptide-1 Receptor Agonist Add-On to Insulin Therapy on Glucose Homeostasis and Body Weight in Patients With Type 1 Diabetes: A Network Meta-Analysis.
Kim, YJ, Hwang, SD, Lim, S
Frontiers in endocrinology. 2020;:553
Abstract
Many patients with type 1 diabetes (T1D) do not achieve the glycemic target goal with insulin treatment. In this study, we aimed to evaluate the efficacy and safety of add-on to insulin therapy in patients with T1D. We conducted direct and indirect network meta-analyses using Bayesian models and ranked hypoglycemic agents via mixed treatment comparison, using data from the CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded databases. Randomized controlled trials (RCTs) involving patients with T1D treated with insulin and add-on metformin or sodium-glucose cotransporter inhibitors or glucagon-like peptide-1 receptor agonists from January 1970 to September 2019 were included in this study. Twenty-three RCTs with 5,151 subjects were divided into the following groups: insulin alone, insulin+metformin, insulin+canagliflozin, insulin+dapagliflozin, insulin+empagliflozin, insulin+sotagliflozin, insulin+liraglutide, and insulin+exenatide. HbA1c level in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group (mean difference: -0.43, 95% credible interval: -0.62 to -0.23). Total daily insulin dose in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group. Compared with that in the insulin alone group, body weight in the groups treated with insulin+add-on canagliflozin, sotagliflozin, and exenatide was significantly decreased by 4.5, 2.8, and 5.1 kg, respectively. Hypoglycemic episodes did not differ among the groups. In patients with T1D, insulin+sotagliflozin decreased the HbA1c level, daily insulin dose, and body weight without hypoglycemia compared with insulin monotherapy. Insulin+canagliflozin or insulin+exenatide was effective in reducing body weight compared with insulin alone. In conclusion, sotagliflozin treatment decreased not only the HbA1c levels and insulin dose but also the body weight without causing hypoglycemia in patients with T1D. Treatment with canagliflozin and exenatide effectively reduced body weight in patients with T1D. However, ketoacidosis associated with the use of SGLT inhibitors should be considered in these patients. Thus, our results suggest that sotagliflozin has a high probability of being ranked first as an adjunctive therapy to insulin in patients with T1D.
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Compelling evidence for SGLT2 inhibitors and GLP-1 receptor agonists as first-line therapy in patients with diabetes at very high/high cardiovascular risk.
Marx, N, Grant, PJ, Cosentino, F
European heart journal. 2020;(2):329-330
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Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases.
Xie, Y, Bowe, B, Gibson, AK, McGill, JB, Maddukuri, G, Yan, Y, Al-Aly, Z
Diabetes care. 2020;(11):2859-2869
Abstract
OBJECTIVE To examine the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes. RESEARCH DESIGN AND METHODS U.S. veterans initiated on SGLT2i (n = 18,544), GLP-1 (n = 23,711), DPP-4 (n = 39,399), or sulfonylureas (n = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores. RESULTS Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR <45 mL/min/1.73 m2. Compared with DPP-4, both SGLT2i and GLP-1 exhibited a reduced risk of the composite outcome in eGFR <90 to ≥60, <60 to ≥45, and <45 mL/min/1.73 m2. CONCLUSIONS In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.
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Effects of glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors on major adverse cardiovascular events in type 2 diabetes by race, ethnicity, and region: A meta-analysis.
Qiu, M, Ding, L, Wei, X, Wei, W, Zhou, H
Medicine. 2020;(49):e23489
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Abstract
BACKGROUND The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists on major adverse cardiovascular events (MACE) in type 2 diabetic subgroups defined by race, ethnicity, and region are unestablished. METHODS We searched PubMed and Embase for related randomized controlled trials. We conducted random-effects meta-analysis, stratified by drug class, on MACE in various subgroups defined by 3 factors of interest (ie, race, ethnicity, and region) to estimate pooled hazard ratio (HR) and 95% confidence interval. Random-effects meta-regression was conducted to evaluate the differences between 2 drug classes. RESULTS We included 11 randomized controlled trials for pooled analysis. Compared with placebo, SGLT2is and GLP-1 RAs significantly reduced the risk of MACE (HR ranged from 0.76 to 0.93) in most diabetic subgroups defined by 3 factors of interest. The 2 drug classes did not significantly reduced this risk in the Black race group (HR 0.92, 95% confidence interval 0.70-1.20). The effect of the 2 drug classes on MACE was not significantly different in all diabetic subgroups of interest (P-value for subgroup differences ranged from .101 to .971). CONCLUSIONS SGLT2is and glucagon-like peptide 1 receptor agonists can significantly reduce the risk of MACE in most type 2 diabetic subgroups defined by race, ethnicity, and region, whereas they fail to do it in Black individuals.
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Oral Semaglutide: First-in-Class Oral GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes Mellitus.
Cowart, K
The Annals of pharmacotherapy. 2020;(5):478-485
Abstract
Objective:The purpose of this article is to review the pharmacological characteristics and clinical evidence of oral semaglutide for the treatment of type 2 diabetes mellitus (T2DM). Data Sources: A MEDLINE/PubMed search was conducted between January 1, 2005, and September 30, 2019. Search terms included semaglutide, glucagon-like peptide 1 receptor agonist, GLP-1 receptor agonist, and type 2 diabetes. Study Selection and Data Extraction Quantification: The following study designs were included in the analysis: systematic review and/or meta-analyses, clinical trial, or observational study design. Narrative reviews were excluded. Articles were included only if they were published in the English language or evaluated oral semaglutide with regard to pharmacology, pharmacokinetics, safety, and efficacy in humans. Data Synthesis: Oral semaglutide has been Food and Drug Administration approved for the treatment of T2DM as an adjunct to diet and exercise. Oral semaglutide has been shown to result in an absolute hemoglobin A1C reduction between -0.5% and -1.5% and weight reductions between -1 and -4.7 kg. Oral semaglutide has been shown to be noninferior to placebo for cardiovascular (CV) safety although additional CV outcomes trials are ongoing. Adverse effects appear to be similar to those of other glucagon-like peptide-1 receptor agonists and are gastrointestinal in nature. Relevance to Patient Care and Clinical Practice: Oral semaglutide may be appropriate as second- or third-line add-on therapy for patients with T2DM who are not meeting treatment goals on metformin and are overweight and reluctant to use an injectable drug. Conclusions: Oral semaglutide appears safe and effective as monotherapy and add-on pharmacological therapy for the treatment of T2DM.