Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus

Background and aimsNonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). There is currently no approved treatment for NAFLD. The main aim was the evaluation of the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) vs. dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment on noninvasive indices of hepatic steatosis and fibrosis in patients with T2DM.MethodsIn this retrospective study, three noninvasive indices of hepatic steatosis [HSI, NAFLD ridge score, and triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio] and five of fibrosis (APRI, FIB-4, NAFLD fibrosis score, BAAT and BARD) were calculated before and after (6–18 months) the addition of a DPP-4i (n = 152) or a GLP-1 RA (n = 37) in patients with T2DM.ResultsRegarding steatosis indices, NAFLD ridge score was significantly decreased in the GLP-1 RA group (baseline: 0.90 ± 0.34, follow-up: 0.67 ± 0.24; p = 0.001), but not in the DPP-4i group (p = 0.25); the difference for group1time interaction was significant (p = 0.02). HSI showed a trend between groups, being significantly different at baseline and follow-up (p < 0.001) with no significant difference in group1time interaction. Indices of fibrosis were not essentially changed within or between groups.ConclusionsNAFLD ridge score was significantly decreased after the addition of GLP-1 RA in patients with T2DM. This study warrants further prospective clinical trials.     

Effects of glucagon-like peptide-1 receptor agonists on major coronary events in patients with type 2 diabetes

Aims

To perform a meta-analysis to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major coronary events, including myocardial infarction (MI), unstable angina and coronary revascularization, in patients with type 2 diabetes mellitus (T2DM).

Materials and methods

We systematically searched the PubMed, CENTRAL, EMBASE and clinicaltrial.gov databases to seek eligible studies with a cardiovascular endpoint comparing GLP-1RAs with a placebo in T2DM patients. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated for the outcomes.

Results

Nine studies, with a total of 64 236 patients, were included. GLP-1RA treatment reduced fatal and nonfatal MI by 8% (OR 0.92, 95% CI 0.86–0.99; P = 0.02, I² = 39%). The reduction reached 15% in human-based GLP-1RA-treated patients. Similarly, once-weekly GLP-1RA treatment reduced the risk of MI by 13%. In contrast, GLP-1RA treatment did not reduce the risk of hospitalization for unstable angina (OR 1.11, 95% CI 0.97–1.28; P = 0.13, I² = 21%). GLP-1RAs exhibited a tendency to lower the risk of coronary revascularization (OR 0.95, 95% CI 0.89–1.02; P = 0.15, I² = 22%), but without statistical significance. Human-based GLP-1RAs decreased the risk by 11%.

Conclusions

In high-risk patients with T2DM, GLP-1RAs were associated with a decrease in MI, especially the human-based and once-weekly GLP-1RAs. No benefit was seen for hospitalization for unstable angina or coronary revascularization. Further research is urgently needed to ascertain improvements in coronary events.     

Cardioprotective properties of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: A systematic review

Background and aimsCardiovascular disease is one of the main contributors for the mortality in type 2 diabetes mellitus (T2DM) patients. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) had shown cardiovascular benefits which may be advantageous to reduce mortality in T2DM patients. This systematic review focused on analyzing the effects of GLP-1 RAs on cardiovascular outcomes.MethodsWe conducted an extensive search through JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. All related studies assessing the use of GLP-1 RAs in T2DM patients from inception up to October 2020 were screened. Any cardioprotective properties as the outcomes were obtained.ResultsA total of six studies (4 randomized, 2 observational) with a total of 182.205 patients were included in this review. The GLP-1 RAs used were either liraglutide or exenatide in combination with antihypertensive or antilipidemic drugs. All studies showed that GLP-1 RA significantly caused weight loss and improved cardiac functional capacity by increasing left ventricular ejection fraction and reducing end-systolic and end-diastolic left ventricle volume. GLP-1 RA also improved myocardial blood flow without affecting myocardial glucose uptake. However, GLP-1 RA failed to show its effect in reducing blood pressure and improving lipid profiles.ConclusionsDespite the limited number of studies, consistent data showed that GLP-1 RA has several cardioprotective properties.     

Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.     

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide,and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms ‘glucagon-like peptide-1 receptor agonist’, ‘glucagon receptor agonist’, ‘glucose-dependent insulinotropic peptide’, ‘dual or co-agonist’, and ‘tirzepatide’. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.     

从肠促胰素分泌机制看胰升糖素样肽1在2型糖尿病治疗中的应用

近年来在2型糖尿病发病机制及治疗领域研究中,肠促胰素是一大突破.本文以肠促胰素分泌生理机制、病理变化到临床应用为线索,简要介绍了营养物质(葡萄糖、脂肪和蛋白质)触发肠促胰素分泌机制、2型糖尿病患者肠促胰素分泌障碍以及一种重要的肠促胰素--胰升糖素样肽1在2型糖尿病治疗中的应用.

Abstract：

Recently, in the field of pathogenesis and treatment of type 2 diabetes, incretin is a major breakthrough. Based on the knowledge about physiological mechanism, pathological characters, and clinical application, this review article summarized the mechanism of nutrients ( glucose, fat, and protein) mediated incretin secretion, the impairment of incretin secretion and action in type 2 diabetes and glucagon-like peptide-1 's use in type 2 diabetic patients.     

The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.     

Association between glucagon-like peptide-1 receptor gene polymorphisms and metabolic markers in type 2 diabetic patients

正Objective To investigate the distribution of polymorphisms of glucagon-like peptide-1 receptor gene (GLP-1R) rs10305420 and rs3765467 in Chinese Han type 2diabetic patients,and the effects on body weight,blood glucose and serum lipid levels.Methods Two SNPs of GLP-1R rs3765467 and rs10305420 were genotyped by Sanger dideoxy termination sequencing method.The ra-     

Efficacy and adherence of glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes mellitus in real-life settings

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary.     

Effects of glucagon-like peptide-1 receptor agonists on kidney function and safety in type 2 diabetes patients

Glucagon‐like peptide‐1 receptor agonists have been recommended in diabetic kidney disease patients.

Type 2 diabetes mellitus is the leading cause of chronic kidney disease (CKD) and almost 40% of type 2 diabetes patients develop diabetic kidney disease (DKD), which is characterized by reduced estimated glomerular filtration rate (eGFR) and/or increased albuminuria. Patients with DKD are at high risk of cardiovascular disease and cardiovascular death; therefore, renal protection strategies are very important for type 2 diabetes patients.Renin–angiotensin–aldosterone system (RAAS) inhibitors are well‐known, classic drugs for DKD therapy. Recently, several clinical trials have reported that some newer glucose‐lowering drugs, including sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), have beneficial effects on the kidneys in type 2 diabetes patients. Currently, there are five GLP‐1RAs (exenatide, lixisenatide, liraglutide, dulaglutide and semaglutide) approved in the USA and Europe. All GLP‐1RAs have shown cardiovascular benefits and safety. Most of these trials have secondary exploratory renal end‐points data, and the secondary renal outcomes from GLP‐1RA cardiovascular outcome trials suggest a renal protective effect of GLP‐1RA ¹ . Based on the previous trial results, GLP‐1RAs have been recommended in DKD patients if they are contraindicated for or do not tolerate SGLT2 inhibitors.Mann et al. ² published an article, “Effects of once‐weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post‐hoc analysis of the SUSTAIN 1–7 randomised controlled trials”’ in The Lancet Diabetes & Endocrinology in November 2020. They carried out a post‐hoc analysis of type 2 diabetes patients enrolled in Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1–7 trials, to investigate the effects of once‐weekly subcutaneous semaglutide 0.5 and 1.0 mg versus comparators on kidney function and safety. The main outcomes were eGFR, urine albumin‐to‐creatinine ratio (UACR) and reported kidney adverse events. Comparators varied between trials: a placebo was used in SUSTAIN 1, 5 and 6; sitagliptin was used in SUSTAIN 2; exenatide extended release in SUSTAIN 3; insulin glargine in SUSTAIN 4; and dulaglutide was used in SUSTAIN 7.In SUSTAIN 1–5 and 7, in all active treatments, the declines in eGFR were observed from baseline to week 12; estimated treatment differences (ETD) compared with placebo were −2.15 (95% confidence interval [CI] −3.47 to −0.83) mL/min per 1.73 m² with semaglutide 0.5 mg, and −3.00 (95% CI −4.31 to −1.68) with semaglutide 1.0 mg; eGFR plateaued after 12 weeks. Also, a greater reduction in eGFR was observed from baseline to the end of treatment when semaglutide was used rather than a placebo (ETD −1.58, 95% CI −2.92 to −0.25 with semaglutide 0.5 mg, and −2.02, 95% CI −3.35 to −0.68 with semaglutide 1.0 mg). In SUSTAIN 6, there was a greater reduction in eGFR from baseline to week 16 when semaglutide was used rather than a placebo (ETD −1.29, 95% CI 2.07 to −0.51 with semaglutide 0.5 mg, and −1.56, 95% CI −2.33 to −0.78 with semaglutide 1.0 mg). However, from baseline to week 104, there was no significant difference in eGFR reduction between semaglutide and the placebo (ETD 0.07, 95% CI −0.92 to 1.07 with semaglutide 0.5 mg, and 0.97, 95% CI −0.03 to 1.97 with semaglutide 1.0 mg; Table ​Table1).1). In SUSTAIN 1–5, at the end of treatment, semaglutide had a greater reduction in UACR compared with the placebo (estimated treatment ratios 0.74, 95% CI 0.64–0.85 for semaglutide 0.5 mg, and 0.68, 95% CI 0.59–0.78 for semaglutide 1.0 mg). In SUSTAIN 6, at the end of treatment, there was as greater reduction in UACR with semaglutide compared with the placebo (estimated treatment ratios 0.75, 95% CI 0.66–0.85 for semaglutide 0.5 mg, and 0.66 95% CI 0.58–0.75 for semaglutide 1.0 mg). There was no difference in the incidence of renal adverse events between the treatment groups and the trials.Table 1Changes and estimated treatment differences in estimated glomerular filtration rate in Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 1–7 used in report form by Mann et al. ²

Determinants of response to the glucagon-like peptide-1 receptor agonists in a type 2 diabetes population in the real-world

AimsTo identify clinical predictors associated with a response in terms of glycemic control and weight loss in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs).MethodsA retrospective observational study was performed with real-world databases in primary care. Patients with type 2 diabetes-initiated treatment with GLP-1RAs during the study period, and response to GLP-1RAs were determined six months from treatment initiation. An optimal glycated hemoglobin (HbA1c) or weight response was defined as a reduction of ≥ 1% or ≥ 3%, respectively. A “great” response was defined as both an optimal HbA1c and weight response. Bivariate and multivariate analyses with intention-to-treat were performed.ResultsA sample of 2944 patients with type 2 diabetes was recruited. Higher HbA1c at baseline was the main clinical predictor of an optimal HbA1c response (odds ratio [OR]: 2.30, 95% confidence interval [CI]: 1.96–2.71 in men and OR: 2.03, 95% CI: 1.76–2.33 in women). Treatment without insulin at baseline was associated with a greater weight reduction in men (OR: 2.50, 95% CI: 1.41–4.44). Older age and a higher weight at baseline were related with this in women (OR: 1.02, 95% CI: 1.00–1.05 and OR: 1.01, 95% CI: 1.00–1.02, respectively).ConclusionsA high HbA1c at baseline and previous non-insulin therapy were the main predictors of a greater response (optimal HbA1c and weight response) to GLP1ra in both men and women. This may aid in treatment decision-making before initiating treatment with GLP-1RAs.     

All-cause mortality in patients with diabetes under glucagon-like peptide-1 agonists: A population-based,open cohort study

AimThe glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting.MethodsWe conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015. Patients with T2DM exposed to GLP1a (n = 8345) were compared to age, gender, body mass index, duration of T2DM and smoking status-matched patients with T2DM unexposed to GLP1a (n = 16,541).ResultsPatients with diabetes receiving GLP1a were significantly less likely to die from any cause compared to matched control patients with diabetes (adjusted incidence rate ratio [aIRR]: 0.64, 95% CI: 0.56–0.74, P-value < 0.0001). Similar findings were observed in low-risk patients (aIRR: 0.64, 95% CI: 0.53–0.76, P -value = 0.0001). No significant difference in the risk of incident CVD was detected in the low-risk patients (aIRR: 0.93, 95% CI: 0.83–1.12). Subgroup analyses suggested that effect is persistent in the elderly or across glycated haemoglobin categories.ConclusionsGLP1a treatment in a real-world setting may confer additional mortality benefit in patients with T2DM irrespective of their baseline CVD risk, age or baseline glycated haemoglobin and was sustained over the observation period.     

Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists

We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.