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Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes.
Meiring, S, Meessen, ECE, van Baar, ACG, Holleman, F, Nieuwdorp, M, Olde Damink, SW, Schaap, FG, Vaz, FM, Groen, AK, Soeters, MR, et al
American journal of physiology. Endocrinology and metabolism. 2022;(2):E132-E140
Abstract
Duodenal mucosal resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signaling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signaling [e.g., via fibroblast growth factor 19 (FGF19)], and are linked to metabolic health. We investigated the effect of DMR and glucagon-like peptide-1 (GLP-1) on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at the baseline and 6 mo after the DMR procedure. The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all P < 0.05), an overall increased secondary bile acid response (P = 0.036) and a higher 12α-hydroxylated:non-12α-hydroxylated ratio (P < 0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-α-hydroxy-4-cholesten-3-one (C4) concentrations decreased postintervention (both P < 0.01). Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids.NEW & NOTEWORTHY Glycemic and metabolic improvements are seen in patients with type 2 diabetes after replacing their insulin therapy with DMR and GLP-1. These changes are accompanied by changes in postprandial bile acid concentrations: increased unconjugated and secondary bile acids.
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Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD.
Farmer, RE, Beard, I, Raza, SI, Gollop, ND, Patel, N, Tebboth, A, McGovern, AP, Kanumilli, N, Ternouth, A
Clinical therapeutics. 2021;(2):320-335
Abstract
PURPOSE Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). METHODS Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FINDINGS Around 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9-9.1%) and 8.9% (8.6-9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0-19.5%) and 21.2% (20.6-21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0-24.4%) and 25.9% (25.2-26.6%) in January 2017 to 41.3% (39.5-43.0%) and 45.5% (44.7-46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. IMPLICATIONS Although use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit.
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Cardiorenal and other diabetes related outcomes with SGLT-2 inhibitors compared to GLP-1 receptor agonists in type 2 diabetes: nationwide observational study.
Lugner, M, Sattar, N, Miftaraj, M, Ekelund, J, Franzén, S, Svensson, AM, Eliasson, B
Cardiovascular diabetology. 2021;(1):67
Abstract
BACKGROUND Major prospective randomized clinical safety trials have demonstrated beneficial effects of treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) in people with type 2 diabetes and elevated cardiovascular risk, and recent clinical treatment guidelines therefore promote early use of these classes of pharmacological agents. In this Swedish nationwide observational study, we compared cardiorenal outcomes and safety of new treatment with GLP-1RA and SGLT-2i in people with type 2 diabetes. METHODS We linked data from national Swedish databases to capture patient characteristics and outcomes and used propensity-score based matching to account for differences between the two groups. The treatments were compared using Cox regression models. RESULTS We identified 9648 participants starting GLP-1RA and 12,097 starting SGLT-2i with median follow-up times 1.7 and 1.1 years, respectively. The proportion of patients with a history of MACE were 15.8%, and 17.0% in patients treated with GLP-1RA and SGLT-2i, respectively. The mean age was 61 years with 7.6 years duration of diabetes. Mean HbA1c were 8.3% (67.6 mmol/mol) and 8.3% (67.2 mmol/mol), and mean BMI 33.3 and 32.5 kg/m2 in patients treated with GLP-1RA or SGLT-2i, respectively. The cumulative mortality risk was non-significantly lower in the group treated with SGLT-2i, HR 0.78 (95% CI 0.61-1.01), as were incident heart failure outcomes, but the risks of cardiovascular or renal outcomes did not differ. The risks of stroke and peripheral artery disease were higher in the SGLT-2i group relative to GLP-1RA, with HR 1.44 (95% CI 0.99-2.08) and 1.68 (95% CI 1.04-2.72), respectively. CONCLUSIONS This observational study suggests that treatment with GLP-1RA and SGLT-2i result in very similar cardiorenal outcomes. In the short term, treatment with GLP-1RA seem to be associated with lower risks of stroke and peripheral artery disease, whereas SGLT-2i seem to be nominally associated with lower risk of heart failure and total mortality.
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Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus.
Guarnotta, V, Bianco, MJ, Vigneri, E, Panto', F, Lo Sasso, B, Ciaccio, M, Pizzolanti, G, Giordano, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(11):3193-3201
Abstract
BACKGROUND AND AIMS To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment. METHODS AND RESULTS Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ_irisin) was significantly related to the changes in total-cholesterol (Δ_total-cholesterol) (r = -0.293; p = 0.020), while the change in IL-6 (Δ_IL-6) was significantly related to the changes in WC (Δ_WC) (r = 0.347; p = 0.006). CONCLUSIONS Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC.
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Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study.
van Dalem, J, Driessen, JHM, Burden, AM, Stehouwer, CDA, Klungel, OH, de Vries, F, Brouwers, MCGJ
Hepatology (Baltimore, Md.). 2021;(5):2467-2477
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Abstract
BACKGROUND AND AIMS Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. APPROACH AND RESULTS We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). CONCLUSIONS Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.
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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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Weight Outcomes With Empagliflozin as Compared With Liraglutide in Veterans With Type 2 Diabetes Mellitus.
Grabarczyk, TR, Wissman, NK
The Annals of pharmacotherapy. 2020;(10):981-987
Abstract
BACKGROUND Glucagon-like peptide-1 agonists and sodium glucose cotransporter 2 inhibitors are associated with weight loss and improved cardiovascular outcomes, and are increasingly used in pharmacotherapy for type 2 diabetes mellitus (T2DM). OBJECTIVES To compare weight loss outcomes of empagliflozin and liraglutide in patients with T2DM and overweight/obesity not yet prescribed insulin but requiring additional pharmacotherapy to improve glycemic control. METHODS This is an observational, multisite, cohort study of veterans with T2DM prescribed liraglutide or empagliflozin. Participants were prescribed either empagliflozin or liraglutide prior to November 1, 2017, had a hemoglobin A1C (A1C) ≥7.0%, had a body mass index ≥27 kg/m2, and were not treated with insulin at baseline. The primary outcome was change in weight after 1 year using multiple regression. Secondary outcomes were the proportion achieving ≥5% weight loss and change in A1C. RESULTS Weight loss was not significantly different between groups: -2.17 kg (95% CI: -2.91 to -1.42) in the liraglutide group (n = 298) and -2.81 kg (95% CI: -3.43 to -2.20) in the empagliflozin group (n = 247; P > 0.05). After adjusting for covariates, this effect remained nonsignificant. There was no difference in change in A1C between liraglutide (-0.83%; 95% CI: -1.05% to -0.62%) and empagliflozin (-0.71%; 95% CI: -0.89% to -0.53%; P > 0.05). CONCLUSIONS AND RELEVANCE There was no significant difference in weight outcomes after 1 year in veterans treated with liraglutide versus empagliflozin. Because both medications did show modest weight loss, both remain good options for patients needing an additional medication to improve glycemic control that is at least weight neutral.
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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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Combination Therapy With Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Older Patients With Type 2 Diabetes: A Real-World Evidence Study.
Carretero Gómez, J, Arévalo Lorido, JC, Gómez Huelgas, R, García de Lucas, D, Mateos Polo, L, Varela Aguilar, JM, Seguí Ripoll, JM, Ena, J, ,
Canadian journal of diabetes. 2019;(3):186-192
Abstract
OBJECTIVES Scientific literature about the combination of glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients is scarce. We sought to assess the real-world efficacy and safety of SGLT2 inhibitors and GLP-1ra combination therapy in older patients (>65 years of age). METHODS This was an observational, prospective, multicenter study based on clinical practice. Patients were stratified according to tertiles of baseline glycated hemoglobin (A1C) levels and to treatment schedule. RESULTS We included 113 patients (65.5% men, mean age 70.4±8.8 years). The body mass index was 36.5 (±6.6) kg/m2. The baseline A1C level was 8.0% (±1.2%). At the 6-month follow up, we found a significant reduction in A1C levels (-1.1%; p<0.0001), body mass index (-2.1 kg/m2; p<0.00003) and systolic blood pressure (-13 mmHg; p<0.000005). Patients who had the highest baseline A1C levels (≥8.4%) showed greater improvement in A1C levels (p<0.0001), weight (p<0.0001) and quality-of-life scores (p<0.0001). The greatest reduction in A1C levels and weight was seen in patients who started both drugs simultaneously (p<0.0001). The second greatest reduction was seen when GLP-1ra was added to previous treatment with an SGLT2i (p<0.0001). Also of note was a decrease in systolic blood pressure in patients for whom an SGLT2i was added to previous GLP-1ra treatment (p<0.0001). Of the patients, 34.3% achieved the combined endpoint of A1C levels <7% and weight loss ≥5% without hypoglycemia. CONCLUSIONS This study's findings provide evidence of clinically meaningful reductions in A1C level, body weight and systolic blood pressure in older patients with type 2 diabetes who are taking combined regimens. The dropout and hypoglycemia rates were minimal, and treatment was tolerated well.
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Characteristics Associated with the Choice of First Injectable Therapy Among US Patients With Type 2 Diabetes.
Yu, M, Mody, R, Landó, LF, Shui, A, Kallenbach, L, Slipski, L, de Oliveira, CP
Clinical therapeutics. 2017;(12):2399-2408
Abstract
PURPOSE The objective of this retrospective observational study was to describe and identify clinical and demographic characteristics associated with the choice of first injectable therapy (glucagon-like peptide-1 receptor agonist [GLP-1-RA] or basal insulin) among patients with type 2 diabetes mellitus (T2DM). METHODS This analysis included adults naive to injectable therapy with T2DM who initiated a GLP-1-RA or basal insulin (index date) between November 2014 and February 2016 using data from the Practice Fusion Electronic Health Record database. Patients with T2DM, ≥1 office visit between 6 and 18 months before the index date, and with ≥1 glycosylated hemoglobin (HbA1c) result in the 6-month preindex (baseline) period were included. A generalized boosted regression model was used to determine the patient characteristics most influential in the selection of a GLP-1-RA or basal insulin as first injectable therapy. Sensitivity analysis was performed by using bootstrapped logistic regression. FINDINGS The study included 3546 and 7507 GLP-1-RA and basal insulin initiators, respectively. At baseline, GLP-1-RA initiators were significantly younger (mean, 58 vs 63 years), had lower HbA1c values (mean, 8.2% vs 9.1%), lower Diabetes Complications Severity Index (DCSI) scores (mean, 1.0 vs 1.7), and a higher body mass index (BMI) (mean, 36 vs 33 kg/m2) compared with basal insulin initiators. Variables selected by using the generalized boosted regression model with the highest relative importance (≥5%) in the selection of GLP-1-RA or basal insulin were HbA1c level (20.43%), BMI (17.73%), age (12.21%), prior prescription of a sodium-glucose cotransporter-2 inhibitor (9.17%), and DCSI score (8.39%). The same variables, as well as race, were selected by using stepwise logistic regression in all the bootstrapped samples. Patients who were older (adjusted odds ratio [OR], 0.975 [95% CI, 0.971-0.979]) and had higher HbA1c values (OR, 0.741 [95% CI, 0.721-0.761]) and DCSI scores (OR, 0.870 [95% CI, 0.848-0.892]) were significantly less likely to be prescribed a GLP-1-RA compared with basal insulin. Patients with higher BMI (OR, 1.046 [95% CI, 1.040-1.053]) and previous prescription of sodium-glucose cotransporter-2 inhibitors (OR, 2.633 [95% CI, 2.224-2.982]) were significantly more likely to be prescribed a GLP-1-RA. IMPLICATIONS The clinically relevant differences observed between the 2 patient populations suggest that GLP-1-RAs and basal insulin are prescribed to different types of patients with T2DM. Examining patients' demographic and clinical characteristics may be important in assisting physicians in the choice of patient-centered injectable treatment regimens.