Incretin hormones and type 2 diabetes.

Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.

Gut hormone co-agonists for the treatment of obesity: from bench to bedside.

The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The first such compound, reported in 2009, was based on balanced co-agonism at glucagon and glucagon-like peptide-1 (GLP-1) receptors. Today, several classes of gut hormone co-agonists are in development and advancing through clinical trials, including dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) co-agonists (first described in 2013), and triple GIP-GLP-1-glucagon co-agonists (initially designed in 2015). The GLP-1-GIP co-agonist tirzepatide was approved in 2022 by the US Food and Drug Administration for the treatment of type 2 diabetes, providing superior HbA1c reductions compared to basal insulin or selective GLP-1 receptor agonists. Tirzepatide also achieved unprecedented weight loss of up to 22.5%-similar to results achieved with some types of bariatric surgery-in non-diabetic individuals with obesity. In this Perspective, we summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Meta-analysis of head-to-head clinical trials comparing incretin-based glucose-lowering medications and basal insulin: An update including recently developed glucagon-like peptide-1 (GLP-1) receptor agonists and the glucose-dependent insulinotropic polypeptide/GLP-1 receptor co-agonist tirzepatide.

OBJECTIVE: To assess comparative efficacy, safety and tolerability of injectable incretin-based glucose-lowering medications (IBGLMs) versus basal insulin treatment in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an updated meta-analysis of randomized clinical trials of head-to-head comparisons of IBGLMs (short- and long-acting glucagon-like peptide-1 [GLP-1] receptor agonists [GLP-1RAs] and glucose-dependent insulinotropic polypeptide [GIP]/GLP-1 receptor co-agonist tirzepatide) versus basal insulin using a PubMed database search (April 2022). The primary endpoint was difference in reduction of glycated haemoglobin (HbA1c ) versus baseline between pooled IBGLMs (fixed-effects meta-analysis) and their subgroups (random-effects meta-analysis) versus basal insulin treatment (mean differences). Secondary endpoints were fasting plasma glucose, body weight, HbA1c target achievement, hypoglycaemia, blood pressure and lipids. Risk of bias assessment was performed using Jadad scores and the Risk of Bias tool 2.0. RESULTS: In all, 20 studies, representing 47 study arms and 11 843 patients, were eligible. Compared with basal insulin, IGBLMs lowered HbA1c by 0.48 (0.45-0.52)% more than did basal insulin treatment. This effect was driven by pooled long-acting GLP-1RAs (ΔHbA1c -0.25 [-0.38; -0.11]%) and the only GIP/GLP-1 receptor co-agonist, tirzepatide (pooled doses; ΔHbA1c -0.90 [-1.06; -0.75]%), while short-acting GLP-1RAs were equally effective compared with basal insulin (P = 0.90). All IBGLM subgroups achieved significantly lower body weight versus insulin treatment (-4.6 [-4.7; -4.4] kg), in particular tirzepatide (-12.0 [-13.8; -10.1] kg). IBGLMs significantly reduced hypoglycaemia and blood pressure and improved lipid variables. Risk of bias was low. IBGLM treatment was associated with more nausea, vomiting and diarrhoea and study medication discontinuation. CONCLUSIONS: Recently introduced, highly effective IBGLMs were superior to basal insulin treatment, reinforcing the recommendation that IBGLMs should be considered as the first injectable treatment for most patients with type 2 diabetes.

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction.

Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA1c (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

Insulin clearance and incretin hormones following oral and "isoglycemic" intravenous glucose in type 2 diabetes patients under different antidiabetic treatments.

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

Acute effects of linagliptin on intact and total glucagon-like peptide-1 and gastric inhibitory polypeptide levels in insulin-dependent type 2 diabetes patients with and without moderate renal impairment.

AIMS: To investigate the effect of renal impairment on incretin metabolism in patients with type 2 diabetes mellitus (T2DM) before and after treatment with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin. MATERIALS AND METHODS: Long-standing T2DM patients with normal (estimated glomerular filtration rate [eGFR] >90 mL/min/1.73m2 ) and impaired (eGFR <60 mL/min/1.73m2 ) renal function on stable treatment with insulin were included. Before and after 8 days of treatment with 5 mg linagliptin once daily, patients underwent a 75-g oral glucose tolerance test (OGTT) and total and intact glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide and glucagon concentrations were measured. The primary outcome was the difference between the study groups in change of intact GLP-1 concentrations. RESULTS: Of 115 patients screened, 29 were analysed (15 [51.7%] with and 14 [48.3%] without renal impairment). Renal function differed significantly between the groups (101 ± 11 vs. 47 ± 13 mL/min/1.73m2 ; P < 0.0001), while glycaemic control was similar (glycated haemoglobin 68 ± 5 vs. 66 ± 5 mmol/mol; P = 0.45). Baseline GLP-1 and GIP levels were comparable. Glucose concentrations during the OGTT were significantly lowered by linagliptin treatment in patients with renal impairment (P = 0.017), but not in those with normal renal function (P = 0.17). Treatment with linagliptin resulted in a significant increase in intact GLP-1 and GIP levels in patients with normal (P = 0.048 and P = 0.0001, respectively) and impaired (P = 0.040 and P = 0.0011, respectively) renal function during the OGTT. However, the primary outcome (difference between the groups in change of intact GLP-1 concentrations) was not significant (P = 0.22). Overall, linagliptin was well tolerated. CONCLUSIONS: Treatment with linagliptin increases intact incretin levels in patients with T2DM. Impaired renal function does not compromise the effects of linagliptin on active or total incretin levels as well as on glucagon secretion. Thus, treatment with linagliptin is suitable for patients with T2DM, independently of renal function.

A Prospective, Randomized Trial Testing Different Regimens of Carbohydrate Administration to Prevent Major Reduction in Plasma Glucose Follwing a Standardized Bout of Moderate Physical Activity in Patients with Type 1 Diabetes.

AIM/HYPOTHESIS: It was the aim to prospectively study regimes of "preventive" carbohydrate administration to avoid major reduction in plasma glucose during physical activity. METHODS: 24 patients with type 1 diabetes (age 41±12 years; 11 women, 13 men; BMI 26.5±4.7 kg/m2; HbA1c 9.1±1.5%; insulin dose 0.64±0.22 IU/kg body weight and day) participated in one experiment without physical activity and in three experiments with a 4 km, 60 min hike starting at 2 p.m.. No "preventive" carbohydrates, 2×10 g or 2×20 g carbohydrates (muesli bars) were taken when starting and after 30 min (randomized order). Plasma glucose was determined. RESULTS: Within 30 min after starting physical activity, plasma glucose fell by approximately 70 mg/dl, making additional carbohydrate intake necessary in 70% of the subjects. This drop was not prevented by any regimens of "preventive" carbohydrate intake. After the nadir, plasma glucose rose faster after the 2×20 g carbohydrate regime (the largest amount tested; p=0.0036). With "preventive" administration of carbohydrates, significantly (p<0.05) less additional "therapeutic" carbohydrates needed to be administered in 6 h following the initiation of the hike. CONCLUSIONS/INTERPRETATION: In conclusion, in the setting of 2 h postprandial exercise in type 1 diabetes, preventive carbohydrate supplementation alone will not completely eliminate the risk of brisk falls in plasma glucose concentrations or hypoglycaemic episodes. Else, higher amounts or repeated administration of carbohydrates may be necessary.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER.

BACKGROUND: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes. METHODS: Pooled (n=12 637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline. RESULTS: The median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%-27%; P<0.001). Significant reductions were also observed in by-trial data analyses (P<0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%-40%]; P<0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m2/y (P<0.0001 and P<0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR <60 versus ≥60 mL/min/1.73 m2 (Pinteraction=0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75-0.99]; P=0.039 and HR, 0.80 [95% CI, 0.66-0.97]; P=0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84-1.02]; P=0.10 and HR, 0.89 [95% CI, 0.69-1.13]; P=0.34). In patients with baseline eGFR 30 to <60 mL/min/1.73 m2, the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59-0.85; P=0.0003, Pinteraction=0.017) to 0.54 for 57% reduction (95% CI, 0.36-0.81; P=0.003, Pinteraction=0.035). CONCLUSIONS: In patients with type 2 diabetes, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease.

Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c < 6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.

Treatment of type 2 diabetes: challenges, hopes, and anticipated successes.

Despite the successful development of new therapies for the treatment of type 2 diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors, the search for novel treatment options that can provide better glycaemic control and at reduce complications is a continuous effort. The present Review aims to present an overview of novel targets and mechanisms and focuses on glucose-lowering effects guiding this search and developments. We discuss not only novel developments of insulin therapy (eg, so-called smart insulin preparation with a glucose-dependent mode of action), but also a group of drug classes for which extensive research efforts have not been rewarded with obvious clinical impact. We discuss the potential clinical use of the salutary adipokine adiponectin and the hepatokine fibroblast growth factor (FGF) 21, among others. A GLP-1 peptide receptor agonist (semaglutide) is now available for oral absorption, and small molecules activating GLP-1 receptors appear on the horizon. Bariatric surgery and its accompanying changes in the gut hormonal milieu offer a background for unimolecular peptides interacting with two or more receptors (for GLP-1, glucose-dependent insulinotropic polypeptide, glucagon, and peptide YY) and provide more substantial glycaemic control and bodyweight reduction compared with selective GLP-1 receptor agonists. These and additional approaches will help expand the toolbox of effective medications needed for optimising the treatment of well delineated subgroups of type 2 diabetes or help develop personalised approaches for glucose-lowering drugs based on individual characteristics of our patients.

Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6.

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58-0.95) and 0.79 (0.57-1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW: To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events.

INTRODUCTION: Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1-5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)). RESEARCH DESIGN AND METHODS: Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects. RESULTS: From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10). CONCLUSIONS: In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.

Effects of Lixisenatide Versus Liraglutide (Short- and Long-Acting GLP-1 Receptor Agonists) on Esophageal and Gastric Function in Patients With Type 2 Diabetes.

OBJECTIVE: Short-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short-acting (lixisenatide) and long-acting (liraglutide) GLP-1 RAs. RESEARCH DESIGN AND METHODS: A total of 57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-h pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying (13C-sodium octanoate acid breath test), and gastric acid secretion (13C-calcium carbonate breath test) were analyzed. RESULTS: Gastric emptying half-time was delayed by 52 min (Δ 95% CI 16, 88) with lixisenatide (P = 0.0065) and by 25 min (3, 46) with liraglutide (P = 0.025). There was no difference in the number of reflux episodes (mean ± SEM 33.7 ± 4.1 vs. 40.1 ± 5.3 for lixisenatide and liraglutide, respectively, P = 0.17) or the extent of gastroesophageal reflux (DeMeester score) (35.1 ± 6.7 vs. 39.7 ± 7.5, P = 0.61), with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by -20.7% (-40.6, -0.8) (P = 0.042) with the GLP-1 RAs. CONCLUSIONS: Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs.

The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists.

The effect of dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP-1RAs in non-clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet-induced obese mice versus semaglutide or long-acting GIP analogue alone. Participants [with and without type 2 diabetes (T2DM)] from a phase 1, 4-week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP-1's effect on GE. In participants with and without T2DM, once-weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP-1RAs.

Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients.

BACKGROUND: Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. PATIENTS AND METHODS: Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. ß-cell area, amyloid deposits, and ß-cell apoptosis were quantified by morphometric analysis. RESULTS: The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. CONCLUSIONS: The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.