The cardiovascular effects of GLP-1 receptor agonists beyond obesity and type 2 diabetes: An anti-atherosclerotic action.

Obesity and overweight affect almost one third of the European population. Obesity and its associated conditions, including type 2 diabetes, significantly impact healthcare systems, life expectancy and quality of life. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity, with or without diabetes, has provided an effective alternative to metabolic surgery and dietary interventions. We are now beginning to understand their pleiotropic effects beyond weight loss, such as their favourable impact on cardiovascular profiles. The aim of this review is to summarize available preclinical and clinical data on the beneficial effects of GLP-1 receptor agonists on atherosclerosis and cardiovascular disease which has the potential to substantially broaden the scope of their clinical applications.

Increased glycemic variability in pregnant women with Roux-en-Y gastric bypass compared with sleeve gastrectomy.

INTRODUCTION: Bariatric surgery is associated with adverse pregnancy outcomes such as reduced birth weight and premature birth. One possible mechanism for this is increased glycemic variability (GV) which occurs after bariatric surgery. The objective of this study was to compare the effect of Roux-en-Y gastric bypass (RYGB) versus vertical sleeve gastrectomy (SG) on GV during pregnancy and to investigate the relationships of GV, type of bariatric surgery and maternal and neonatal outcomes. RESEARCH DESIGN AND METHODS: Fourteen pregnant women after RYGB and 14 after SG were investigated with continuous glucose monitoring in their second or third trimester in this observational study carried out as part of routine clinical care. RESULTS: Pregnant women with RYGB had similar mean interstitial glucose values but significantly increased indices of GV and a lower %time in range 3.9-7.8 mmol/L (70-140 mg/dL), compared with SG. CONCLUSIONS: Pregnant women who have undergone RYGB have greater GV during pregnancy compared with those who have undergone SG. Further research is needed to establish the relationship between GV and pregnancy outcomes to determine the preferred bariatric operation in women of reproductive age, and whether interventions to reduce GV might improve outcomes.

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy.

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

Tripeptide gut hormone infusion does not alter food preferences or sweet taste function in volunteers with obesity and prediabetes/diabetes but promotes restraint eating: A secondary analysis of a randomized single-blind placebo-controlled study.

AIMS: To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. RESULTS: Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. CONCLUSION: The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

The postprandial secretion of peptide YY1-36 and 3-36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy.

OBJECTIVES: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1-36 and PYY3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1-36 and PYY3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY1-36 and PYY3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. DESIGN AND SUBJECTS: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1-36 and PYY3-36 concentrations. RESULTS: Presurgery, the fasting and postprandial levels of PYY1-36 and PYY3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1-36 and PYY3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. CONCLUSIONS: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1-36 and PYY3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery.

The Metabolomic Effects of Tripeptide Gut Hormone Infusion Compared to Roux-en-Y Gastric Bypass and Caloric Restriction.

CONTEXT: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery. OBJECTIVE: To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). DESIGN AND SETTING: Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. PATIENTS AND INTERVENTIONS: Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. MAIN OUTCOME MEASURES: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention. RESULTS: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. CONCLUSIONS: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study.

OBJECTIVE: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. RESEARCH DESIGN AND METHODS: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups. RESULTS: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. CONCLUSIONS: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.

Gastrointestinal Peptides as Therapeutic Targets to Mitigate Obesity and Metabolic Syndrome.

PURPOSE OF REVIEW: Obesity affects over than 600 million adults worldwide resulting in multi-organ complications and major socioeconomic impact. The purpose of this review is to summarise the physiological effects as well as the therapeutic implications of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP) in the treatment of obesity and type 2 diabetes. RECENT FINDINGS: Clinical trials have proven that the widely used GLP-1 analogues have pleotropic effects beyond those on weight and glucose metabolism and appear to confer favourable cardiovascular and renal outcomes. However, GLP-1 analogues alone do not deliver sufficient efficacy for the treatment of obesity, being limited by their dose-dependent gastrointestinal side effects. Novel dual agonists for GLP-1/glucagon and GLP-1/GIP are being developed by the pharmaceutical industry and have demonstrated some promising results for weight loss and improvement in glycaemia over and above GLP-1 analogues. Triagonists (for example GLP-1/GIP/glucagon) are currently in pre-clinical or early clinical development. Gastrointestinal hormones possess complementary effects on appetite, energy expenditure, and glucose metabolism. We highlight the idea that combinations of these hormones may represent the way forward in obesity and diabetes therapeutics.

Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study.

INTRODUCTION: Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery. RESEARCH DESIGN AND METHODS: Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the 'Alternative' improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method. RESULTS: After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion. CONCLUSIONS: There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB. TRIAL REGISTRATION NUMBER: NCT01945840.

Roux-en-Y Gastric Bypass Is More Effective than Sleeve Gastrectomy in Improving Postprandial Glycaemia and Lipaemia in Non-diabetic Morbidly Obese Patients: a Short-term Follow-up Analysis.

PURPOSE: We aimed to compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on postprandial glucose and lipid metabolism in addition to weight loss and fasting metabolic profile, in non-diabetic patients undergoing bariatric surgery. METHODS: Seventy-one patients were consecutively recruited and studied preoperatively, 3 and 6 months after surgery. Of these, 28 underwent RYGB (7 males, age 38 ± 9 years, BMI 46.9 ± 5.0 kg/m2), and 43 SG (9 males, age 38 ± 9 years, BMI 50.2 ± 7.0 kg/m2). A semi-liquid mixed meal was consumed, and blood samples were taken before, and every 30 min after meal ingestion up to 180 min postprandially, for measurement of glucose, insulin, and lipids. The overall postprandial response was assessed as area under the concentration-time curve (AUC). RESULTS: Baseline metabolic parameters were similar between RYGB and SG. Both groups experienced comparable weight loss, and a similar improvement in fasting glucose, insulin, and insulin resistance. Total and LDL cholesterol levels were lower at 6 months after RYGB compared to SG, while there was no difference in HDL cholesterol or triglycerides. Glucose AUC was lower after RYGB compared to SG at both 3 (p = 0.008) and 6 months (p = 0.016), without any difference in postprandial insulin response. Triglyceride AUC was also lower in RYGB vs. SG at 3 and 6 months (p ≤ 0.001). CONCLUSIONS: RYGB is superior to SG in improving postprandial glycaemia and lipaemia and cholesterol profile 6 months postoperatively in non-diabetic, severely obese patients. These findings imply procedure-specific effects, such as the malabsorptive nature of RYGB, and less likely a different incretin postoperative response.

Improvement in cardiovascular indices after Roux-en-Y gastric bypass or sleeve gastrectomy for morbid obesity.

BACKGROUND: Morbidly obese patients display cardiac abnormalities which are partially reversed after weight loss. The aim of the present study was to assess the potential difference in cardiovascular disease indices between patients who underwent either gastric bypass surgery or sleeve gastrectomy. METHODS: Thirty-seven morbidly obese patients who underwent either Roux-en-Y gastric bypass (RYGB) (n = 14) or SG (n = 23) were examined before, 3 and 6 months after surgery. Indices of cardiac autonomic nervous system activity were evaluated, namely baroreflex sensitivity (BRS) and heart rate variability (HRV). A complete echocardiographic study was performed in a subgroup of 17 patients (RYGB 8, SG 9) preoperatively and 6 months after surgery, evaluating epicardial fat thickness, aortic distensibility, left ventricular (LV) Tei index, left atrium diameter, ejection fraction, and LV mass. RESULTS: All subjects experienced significant (p < 0.001) and similar weight loss independently of the type of operation. BRS and HRV indices improved significantly and to the same degree after surgery in both groups. In the echocardiographic study, all parameters improved significantly at 6 months in comparison with the baseline values. In addition, the RYGB group displayed significantly greater reduction in epicardial fat thickness (p = 0.007) and also tended to have a better LV performance as expressed by the lower values of the Tei index (p = 0.06) compared to the SG group 6 months after surgery. CONCLUSIONS: Both RYGB and SG exert comparable effects on weight loss and improvement of cardiovascular parameters. RYGB displays a more beneficial influence on epicardial fat thickness and left ventricular performance than SG.

Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study.

OBJECTIVE: Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti-tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition. RESEARCH DESIGN AND METHODS: This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis. RESULTS: Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 +/- 5.1 (mean +/- SD) letters read at baseline to 28.8 +/- 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 +/- 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 +/- 10.3 at baseline to 30.4 +/- 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 +/- 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8-43.7; P = 0.017). Infliximab treatment was well tolerated. CONCLUSIONS: The positive results of this small phase III study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME.