Glucagon-like Peptide-1 Receptor Analogues Research Articles

Time to unshackle the medical treatment of obesity in the NHS

Obesity affects one in four people in the United Kingdom and costs the National Health Service (NHS) ∼£6.5 billion annually. The glucagon-like peptide-1 (GLP-1) receptor analogues, such as once-daily subcutaneous Liraglutide 3.0 mg (Saxenda®) and once-weekly subcutaneous Semaglutide 2.4 mg (Wegovy®), were approved by the National Institute of Health and Care Excellence (NICE) as a treatment for obesity and funded by the NHS for 2 years. Our local data shows that Saxenda is effective at reducing body weight and glycaemia in people with obesity and diabetes; however, the supply issues of GLP-1 receptor analogues have contributed to the unavailability of Saxenda and Wegovy in our service. Our patients are devastated that they cannot access NICE-approved GLP-1 receptor analogues for obesity. The 2-year GLP-1 receptor analogue treatment limit for obesity alongside a lack of funded NHS services and supply issues represent barriers to treatment for people living with obesity who have clear medical indications.

Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial

Introduction: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. Methods: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. Results: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. Conclusions: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide’s pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

A clinical case of asymptomatic pancreatic hyperenzymemia on the background of taking a Glucagon-like peptide-1 analogue (GLP-1)

According to current statistics, the incidence of type 2 diabetes has increased significantly over the past few years. The number of drugs prescribed to correct carbohydrate metabolism is also increasing, and new groups of hypoglycemic drugs are appearing. This prompts a more detailed study and analysis of the possible side effects of the prescribed therapy. One of the modern groups of medications f or treating type 2 diabetes are analogues of glucagon-like peptide-1 receptor agonists, which, in addition to correcting carbohydrate metabolism, have a beneficial effect on the risk of developing cardiovascular events. Despite this, there is evidence that their use may be associated with the development of undesirable adverse effects from the pancreas, particularly acute pancreatitis, pancreatopathy, or asymptomatic hyperenzymemia. The aim of our work was the analysis of a clinical case of an asymptomatic increase in the level of pancreatic enzymes (Gullo's syndrome) in a patient with type 2 diabetes, who used a glucagon-like peptide-1 receptor analogue for treatment according to the usual scheme (dulaglutide 0.75 mg subcutaneously once a week during 2 years). As a result, the patient developed a side effect that could be related to taking this medicine. This did not lead to the withdrawal of the drug but required a more thorough examination of the patient and regular further screening for the timely detection of the development of possible organic pathology of the pancreas in the future. So, after analyzing this clinical case, it is possible to see the possibility of developing asymptomatic pancreatic hyperenzymopathy during the treatment of type 2 diabetes mellitus with glucagon-like peptide-1 receptor agonist analogues, which should be taken into account when determining the treatment tactics.

Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery

Metabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1). To assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. The Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up. Liraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status. The primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events. A total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths. These findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. ClinicalTrials.gov Identifier: NCT03341429.

All-cause mortality and cardiovascular outcomes with sodium-glucose Co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes.

To assess the relationship of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP-1RA) and their combination (SGLT2i + GLP-1RA) with 5-year risk of all-cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes. Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP-1RA and SGLT2i + GLP-1RA) were compared against a control cohort (no SGLT2i/GLP-1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP-1RA, n = 186 841; SGLT-2i + GLP-1RA, n = 108 504). A sub-analysis comparing combination and monotherapy cohorts was also performed. The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all-cause mortality (SGLT2i 0.49, 0.48-0.50; GLP-1RA 0.47, 0.46-0.48; combination 0.25, 0.24-0.26), hospitalization (0.73, 0.72-0.74; 0.69, 0.68-0.69; 0.60, 0.59-0.61) and acute myocardial infarct (0.75, 0.72-0.78; 0.70, 0.68-0.73; 0.63, 0.60-0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub-analysis showed a significant risk reduction in all-cause mortality for combination therapy versus SGLT2i (0.53, 0.50-0.55) and GLP-1RA (0.56, 0.54-0.59). SGLT2i, GLP-1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all-cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5-year all-cause mortality when compared directly against either monotherapy.

Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?

Stroke is a leading cause of disability and death, and people with type 2 diabetes (T2D) have a greater risk of stroke and death or disability from stroke. The underlying pathophysiology associating stroke and T2D is complicated by the association of risk factors for stroke frequently seen in people with T2D. Treatments to reduce the excess risk of new-onset stroke or to improve outcomes in people with T2D following stroke would be of major clinical interest. In practice, the focus of care in people with T2D remains treating risk factors for stroke, such as lifestyle and pharmacological interventions for hypertension, dyslipidemia, obesity, and glycemic control. More recently, cardiovascular outcome trials primarily designed to assess the cardiovascular safety of GLP-1RAs (glucagon-like peptide-1 receptor analogues) have consistently observed a reduced stroke risk in people with T2D. This is supported by several meta-analyses of cardiovascular outcome trials observing clinically important risk reductions in stroke. Moreover, phase II trials have described reductions in poststroke hyperglycemia in people with acute ischemic stroke suggestive of improved outcomes following admission to hospital with acute stroke. In this review, we discuss the increased risk of stroke in people with T2D and outline the key associated mechanisms responsible. We discuss the evidence from cardiovascular outcome trials exploring GLP-1RA use and highlight areas of potential interest for future work in this rapidly developing area of clinical research.

Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management.

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

New therapies for obesity.

Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss (WL) through lifestyle changes results in modest WL long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in ≥ 15% WL and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for the treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4 mg/week-the latest glucagon-like peptide-1 (GLP-1) receptor analogue-on WL for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where ≥15% WL is feasible. Moreover, the WL achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional WL compared with GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies.

Calibrating a network meta-analysis of diabetes trials of sodium glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor analogues and dipeptidyl peptidase-4 inhibitors to a representative routine population: a systematic review protocol

IntroductionParticipants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this,...

Liraglutide treatment attenuates dysfunction-related changes in the cardiac and cerebral microvasculature in streptozotocin-induced diabetic rats

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Background Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 receptor analogue, inhibited the reactive oxygen species producing enzyme NOX2 and adhesion molecules in isolated endothelial cells. Here we have studied how Liraglutide affects advanced glycation, NOX expression and inflammatory status of the cardiac and cerebral microvasculature in vivo in diabetic rats. Methods DM was induced in Sprague Dawley rats (n=15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg body weight). 10 control rats remained non-diabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n=7) or vehicle (n=8) was injected subcutaneously daily until termination on day 29. The advanced glycation end-product N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently analysed using immunohistochemistry and quantified to compare Liraglutide treatment to placebo. Results DM increased CML, NOX2, ICAM-1 and VCAM-1 in the intramyocardial vasculature, although not significant for NOX2. NOX4 was not significantly increased in the ventricles and absent in the atria. In the cerebral vasculature, CML, NOX2 and NOX4 were significantly increased, but not ICAM-1 and VCAM-1. Liraglutide significantly reduced the DM-associated CML accumulation and expression of NOX2, ICAM-1 and VCAM-1 in the intramyocardial, and CML, NOX2 and NOX4 in the cerebral vasculature. Liraglutide had these effects without changing blood glucose levels or body weight. Conclusions Our study implies that Liraglutide protects the cardiac and cerebral microvasculature against diabetes-induced dysfunction, independent of a blood glucose lowering effect in a type 1 diabetes rat model.

Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease.

Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.

Glucagon-like Peptide-1 Receptor Analogues for the Treatment of Obesity.

There is an increasing prevalence of obesity worldwide, associated with significant morbidity and mortality, which frequently reduces quality of life and life expectancy. Consequently, there is a substantial and growing personal and economic burden necessitating the development of more effective therapies for obesity. Glucagon-like peptide-1 receptor analogues (GLP-1RAs) are licensed for the treatment of type 2 diabetes (T2D), and there is substantial evidence that these drugs not only improve cardiovascular outcomes but also promote weight loss. More recent evidence supports the use of the GLP-1RAs liraglutide and semaglutide in people with obesity without T2D. This article discusses the results of the major cardiovascular outcome trials for GLP-1RAs in people with T2D, the SCALE Obesity and Prediabetes study (Effect of liraglutide on body weight in non-diabetic obese subjects or overweight subjects with co-morbidities: SCALE™ - Obesity and Pre-diabetes; ClinicalTrials.gov identifier: NCT01272219; investigating liraglutide) and the STEP studies (Semaglutide treatment effect in people with obesity; assorted studies; investigating subcutaneous semaglutide). We also highlight the importance of a cost-effective approach to obesity pharmacotherapy. Clinicians should consider the use of GLP-1RAs in people with obesity, especially those with T2D or other obesity-related diseases, such as hypertension and dyslipidaemia. Ongoing trials, as well as clinical and cost-effectiveness appraisals, are anticipated over the next 12 months, and their findings may change the current landscape of obesity pharmacotherapy.

Comparison of Therapies with GLP1 Analogues in Type 2 Diabetic Patients Without Control

BackgroundType 2 Diabetes (T2D) is a chronic disease in the aspect of insulin resistance in the adulthood, that requires continuous medical attention and represents a therapeutic challenge beyond glycemic control. Glucagon-like Peptide-1 receptor analogues (GLP-1) have a favorable effect in modifying cardiovascular risk factors. the objective is to analyze the clinical benefits of there. MethodsComparison of three descriptive, retrospective cohort studies, conducted between June-2013 and June-2016, 52 week follow-up, including patients with uncontrolled T2D, with different therapies, who were added to the treatment GLP-1 analogues, in a high complexity center in the city Cali, Colombia. Three specific therapies where compared: Liraglutide 1.8 mg/day; exenatide 2 mg/week, and exenatide 2 mg/week plus dapagliflozin/metformina 10/2000 mg/day, respectively. Repeated measurements were made over time of glycated hemoglobin (A1C), weight, and blood pressure (BP). ResultsThe mean age was 60.6 years. The onset of T2D was 6.2 years. Combination therapy showed an average decrease of: A1C of 1.8% for Liraglutide (IC 95%, 1.52-2.04; P<0.0001), 1.7% for exenatide (IC 95%, 1.45-1.94, p<0.000) and 0.70% for exenatide plus dapagliflozin/metformin (CI 0.58 to 0.82, p <0.001); weight loss of: 5.1 kg, 5.8 kg and 3.04 kg respectively; and decrease of systolic BP of: 6.7mmHg, 15.6 mmHg and 16.3 mmHg, respectively. The largest decrease in A1C occurred between first and second visit and no serious adverse events were observed. ConclusionGLP-1 analogues are a favorable therapeutic option for patients with uncontrolled T2D, with beneficial effect on body weight and BP with statistically significant results.

103-OR: The Glucagon-Like Peptide-1 Analog, Liraglutide Is a Safe and Effective Treatment of Bile Acid Malabsorption: A Proof of Concept Study

Bile acid malabsorption (BAM) is caused by excessive spill-over of bile acids to the colon and is estimated to affect ∼1% of the general population. It is a socially debilitating disease with watery diarrhea and high stool frequency as main symptoms. BAM is diagnosed by the 75selenium homotaurocholic acid test (SeHCAT) measuring the retention of bile acids. Bile acid sequestrant (BAS) treatment, which is the only recommended treatment of BAM, is associated with poor effect and low compliance. Case reports suggest that the glucagon-like peptide 1 receptor analog (GLP-1RA) liraglutide may be an effective treatment of BAM. In this double-blind, double-dummy, non-inferiority study, nondiabetic individuals with SeHCAT-verified BAM, age 18-75 years and BMI 18.5-40 kg/m2 were randomized to receive the GLP-1RA liraglutide (uptitrated to 1.8 mg per day) or the BAS colesevelam (1.875 mg × 2 per day) for 6 weeks prior to a 7-day run-in period without treatment. SeHCAT was made at baseline, week 3 and week 6. The primary outcome was the proportion of patients experiencing a reduction in stool frequency of ≥25% per day. Of 52 randomized subjects (18 males, 34 females, mean age 50.2 years and BMI 29.9 kg/m2), one patient from each group dropped out due to gastrointestinal side effects. At end-of-treatment, 20 (77%) individuals on liraglutide had experienced a reduction in stool frequency of ≥25% per day vs. 13 (50%) on colesevelam treatment, corresponding to a statistically superior risk difference of -0.27 (one-sided 95% CI: -1; -0.06). In contrast to the colesevelam-treated group, the liraglutide-treated group exhibited a significant increase in SeHCAT values resulting in significantly higher values at end-of-treatment (mean (SD) 8.9 (7.3) vs. 0.9 (2.0) %, P&amp;lt;0.0001). In conclusion, we show that liraglutide enhances the reabsorption of bile acids and constitutes a safe and effective treatment of BAM which is superior compared to current standard of care (colesevelam). Disclosure M. L. Kårhus: None. A. Brønden: None. J. Forman: None. A. Haaber: None. E. Langholz: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. D. P. Sonne: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Novo Nordisk Foundation (NNF17OC0029710); A.P. Møller and Chastine Mc-Kinney Møller Foundation (19-L-0002)

Real-World Clinical Experience of Semaglutide in Secondary Care Diabetes: A Retrospective Observational Study.

IntroductionThe glucagon-like peptide-1 receptor analogue (GLP-1RA) semaglutide is associated with improvements in glycaemia and cardiovascular risk factors in clinical trials. The aim of this study was to examine the real-world impact of semaglutide administered by injection in people with type 2 diabetes (T2D) across three secondary care sites in Wales.MethodsA retrospective evaluation of 189 patients with T2D initiated on semaglutide between January 2019 and June 2020 with at least one follow-up visit was undertaken.ResultsAt baseline, participants had a mean age of 61.1 years, mean glycated haemoglobin (HbA1c) of 77.8 mmol/mol (9.3%) and mean body weight of 101.8 kg. At 6 and 12 months of follow-up, mean HbA1c reductions of 13.3 mmol/mol (1.2%) and 16.4 mmol/mol (1.5%), respectively, were observed, and mean weight loss at 6 months was 3.0 kg (all p < 0.001). At 12 months, there were significant reductions in total cholesterol (0.5 mmol/L) and alanine transaminase (4.8 IU/L). Patients naïve to GLP-1RAs or with higher baseline HbA1c at baseline had greater glycaemic reductions, although clinically significant HbA1c reductions were also observed in those who switched from other GLP-1RAs, whose body mass index was < 35.0 and > 35.0 kg/m2 or who had lower baseline HbA1c. Semaglutide was generally well tolerated, although adverse-effects limited use in 18 patients (9.5%).ConclusionSemaglutide provided clinically and statistically significant reductions in HbA1c, body weight, lipids and liver enzymes.

Comparison of Therapies with GLP1 Analogues in Type 2 Diabetic Patients without Control

Abstract Background Type 2 Diabetes (T2D) is a chronic disease in the aspect of insulin resistance in the adulthood, that requires continuous medical attention and represents a therapeutic challenge beyond glycemic control. Glucagon-like Peptide-1 receptor analogues (GLP-1) have a favorable effect in modifying cardiovascular risk factors. the objective is to analyze the clinical benefits of there. Methods Comparison of three descriptive, retrospective cohort studies, conducted between June-2013 and June-2016, 52 week follow-up, including patients with uncontrolled T2D, with different therapies, who were added to the treatment GLP-1 analogues, in a high complexity center in the city Cali, Colombia. Three specific therapies where compared: Liraglutide 1.8 mg/day; exenatide 2 mg/week, and exenatide 2 mg/week plus dapagliflozin/metformina 10/2000 mg/day, respectively. Repeated measurements were made over time of glycated hemoglobin (A1C), weight, and blood pressure (BP). Results The mean age was 60.6 years. The onset of T2D was 6.2 years. Combination therapy showed an average decrease of: A1C of 1.8% for Liraglutide (IC 95%, 1.52-2.04; P Conclusion GLP-1 analogues are a favorable therapeutic option for patients with uncontrolled T2D, with beneficial effect on body weight and BP with statistically significant results.

The Body Weight Alteration and Incidence of Neoplasm in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

ObjectiveWhether hypoglycemic treatments with weight-alternating effects influence the incidence of neoplasm in type 2 diasbetes (T2D) remains uncertain. Therefore, we performed a meta-analysis to assess the association between the weight alteration and incidence of neoplasm in patients with T2D.Research Design and MethodsSystematic searches were conducted for studies published between the inception of 1950s and September 2019. Randomized controlled trials conducted in T2D patients with at least 48-week follow-up, significant weight change difference between treatment arms and reports of neoplasm events were included. Fixed-effects model and meta-regression analysis were accordingly used.ResultsIn all, 46 studies were included. Analysis indicated weight reduction was not associated with a decreased incidence of neoplasm (OR = 1.01, 95% CI, 0.96 to 1.07, I2 = 17%) and weight elevation was not associated with an increased incidence of neoplasm (OR = 0.91, 95% CI, 0.76 to 1.09, I2 = 0%). Meta-regression analysis showed a slower weight reduction rate (β = −5.983, 95% CI, −11.412 to 0.553, P = 0.03) instead of weight change difference (β = −0.030, 95% CI, −0.068 to 0.007, P = 0.115) was significantly associated with reduced risk of neoplasm in patients with T2D. Moreover, a decreased incidence of prostate, bladder, and uterine neoplasm was observed in T2D patients with weight reduction difference while an increased incidence of thyroid neoplasm was found in glucagon-like peptide-1 receptor analog (GLP-1RA) users with weight reduction difference.ConclusionsAdditional weight change achieved by current hypoglycemic agents or strategies in short and medium periods was not associated with incidence of most neoplasm in patients with T2D. However, a decreased incidence of prostate, bladder, and uterine neoplasm was shown in T2D patients with weight reduction difference while an increased risk of thyroid neoplasm was observed in T2D patients on GLP-1RA treatments with weight reduction difference. A more sustained and persistent weight reduction process may confer reduced risk of neoplasm in patients with T2D.

Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues.

Glucagon-like peptide- 1 receptor analogs (GLP-1RAs) are incretin mimetics with potent glucose-dependent insulinotropic action that translates to glycemic control in people with type- -2 diabetes mellitus (T2DM). These agents potentially have the ability to stimulate proliferation or prevent apoptosis of pancreatic β-cells, induce weight-loss and provide vascular benefits in patients with T2DM. Newer GLP-1RA, semaglutide has shown a robust reduction in HbA1c up to 1.5 - 1.8%. However, individual differences exist between the different GLP-1RAs, in terms of efficacy, pharmacokinetics, tolerability, and vascular protection. The potential of vascular protection offered by newer anti-diabetic agents has generated a lot of excitement in the field of diabetes, and to a large extent, is now driving treatment decisions. So far, six cardiovascular outcome trials of GLP-1 RAs have been published, analyzing lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), long-acting exenatide (EXSCEL), dulaglutide (REWIND), and oral semaglutide (PIONEER 6) with a follow-up duration of 2-4 years. LEADER, REWIND and SUSTAIN-6 trials have demonstrated a reduction in rates of major adverse cardiovascular events with active GLP-1 RA treatment, but ELIXA, PIONEER 6 and EXSCEL, have been neutral. In this review, we discuss the available evidence from randomized controlled trials (RCTs) analyzing the cardiovascular effects of various GLP-1 RAs with the aim of comparing individual drugs. We have also summarized the general aspects of GLP-1RAs that can be applied in clinical practice.

Stroke and myocardial infarction prevention with GLP1 analogues in high or very-high cardiovascular risk diabetic patients

Abstract Background Patients with established cardiovascular disease have an increased risk of stroke, even in the absence of atrial fibrillation. Several trials have analysed the effect of glucagon-like peptide-1 receptor (GLP1) analogues on cardiovascular events in patients with high cardiovascular disease. Methods We performed a metanalysis with all randomized clinical trial that compared a GLP1 analogue vs. placebo. Primary endpoint was stroke incidence, including ischemic and haemorrhagic aetiology, assessed by fixed-effect model. Results We identified 7 trials that compared a GLP analogue (albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide). A total of 56,004 patients were included in the analysis, 27977 treated with a GLP1 analogue. Mean age of the patients was 63.9 (2.1) years, 25,398 (45.4%) patients had cardiovascular disease. A total of 1,568 strokes were reported, 711 in patients receiving a GLP analogue and 857 in control arm; treatment with a GLP1 analogue reduced the incidence of stroke by 147% (RR: 0.83, 95% CI 0.75–0.92; p&amp;lt;0.001). No heterogeneity between trials was observed (p=0.835). Globally, treatment with GPL1 analogues reduced the incidence of stroke or myocardial infarction by 11% (RR: 0.89, 95% CI 0.84–0.94; p&amp;lt;0.01) A total of 3,192 cases of myocardial infarction were reported: 1,524 in patients treated with GLP1 analogues and 1,668 with placebo. Treatment with GLP1 analogues reduce the incidence of myocardial infarction by 8% (RR: 0.92, 95% CI 0.86–0.98; p=0.010) Conclusions Treatment with a GLP1 analogue reduced the incidence of stroke by 17% and myocardial infarction by 8%, in different trials involving high or very-high risk patients with diabetes. Forest plot: stroke and MI Funding Acknowledgement Type of funding source: None

Elderly Diabetic Patients with Effective Add-on Therapy of Dulaglutide as a GLP-1 Receptor Analogue (GLP-1 RA)

Background: For diabetic treatment, Dulaglutide has been used and effective as a glucagon-like peptide-1 receptor analogue (GLP-1 RA). This report is to describe the various responses and to analyze dulaglutide administration in the elderly with DM. Case presentation: Two patients were Type 2 Diabetes Mellitus (T2DM) treated with add-on therapy of Dulaglutide. Case 1 is 81-year-old female is diabetic for 2 years, and on Metformin and Glimepiride as Oral Hypoglycemic Agents (OHAs). Her HbA1c was higher with 10.6% and she was started to given Dulaglutide 0.75mg. Remarkable efficacy was found in 3 months with HbA1c 6.7%. Value of LDL-C increased from 135 mg/dL to 158 mg/dL. Case 2 is 83-year-old male with 27 years of diabetes. He was on medication of Metformin and Glimepiride. His HbA1c persisted around 9.0%-9.4%, then he was provided Dulaglutide as add-on therapy. In 3 months, HbA1c decreased to 8.2% and LDL-C increased from 57 mg/dL to 116 mg/dL. Discussion and conclusion: Dulaglutide is a useful GLP-1 RA with once a week administration. There were some reports concerning LDL changes after dulaglutide therapy, showing that the changes may depend on the basal LDL value before the administration of dulaglutide. Dulaglutide may influence lipid metabolism. This report is expected to become reference in diabetic practice and research in the future.