[Gastrointestinal hormones: their increasing pharmacotherapeutic relevance in metabolic diseases]. / Gastrointestinale Hormone ­ zunehmende arzneitherapeutische Bedeutung bei Stoffwechselerkrankungen.

Gastrointestinal hormones play an important role in the endocrine communication between the intestine, the pancreas, the liver and the brain. Glucagon-like peptide­1 receptor agonists (GLP-1RA) are established therapeutic agents in the treatment of type­2 diabetes. Multiple agonists acting as ligands on various gastrointestinal hormone receptors are a novel pharmacological development. In addition to glucagon-like peptide 1 (GLP-1), these multiple agonists also have glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptors as target structures for their pharmacological action. The multiple agonist action is designed to increase glycaemic effects as well as the effects on body weight. This article provides an overview of GLP-1RA and the multiple agonists. Among the dual agonists, the GIP/GLP-1-agonist tirzeptide has been approved for the treatment of type­2 diabetes, and clinical studies with tirzepatide as a treatment for obesity are ongoing. The currently available data on studies with GLP-1/glucagon agonists and triple agonists are also summarized.

Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity.

Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) are already established in the treatment of type 2 diabetes (T2D). The development of novel dual- or triple-receptor agonists that bind to the receptors not only for GLP-1 but also to the receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon is intended to address different metabolic pathways for carbohydrate, lipid, and protein metabolism simultaneously. Dual- and triple-receptor agonists acting via different receptors and postreceptor pathways seem attractive in view of potentially additive or synergistic effects in the treatment of T2D and obesity. Recently, the first approval for a dual-receptor agonist marks an important step in this development. The GIP/GLP-1-receptor agonist tirzepatide was approved for the treatment of T2D by the Food and Drug Administration (FDA) in the USA for once-weekly subcutaneous injections in May 2022 and has just received a positive opinion from the European Medicines Agency (EMA). Tirzepatide dose-dependently leads to clinically significant reductions in glycemic parameters and body weight and has been shown to have stronger effects in reducing these parameters than standard antidiabetic therapy. This article summarizes the current clinical study program and the respective outcomes and highlights further potential indications for tirzepatide in the treatment of obesity and potentially other comorbidities of T2D.

The incretin/glucagon system as a target for pharmacotherapy of obesity.

Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.

Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide.

Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Effect of once-weekly dulaglutide on glycated haemoglobin (HbA1c) and fasting blood glucose in patient subpopulations by gender, duration of diabetes and baseline HbA1c.

AIMS: To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD-1 to -6 and -8 clinical trials). METHODS: Change in HbA1c was analysed by gender, duration of diabetes (<5, ≥5 years and <10, ≥10 years), and baseline HbA1c (<8.5%, ≥8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials. RESULTS: In the pooled analysis of patients treated with dulaglutide 1.5 mg at 6 months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean -1.26% [95% confidence interval {CI} -1.36, -1.16]; women: LS mean -1.33% [95% CI -1.43, -1.24]) and among duration of diabetes subgroups (<5 years: LS mean -1.32% [95% CI -1.43, -1.22]; ≥5 and <10 years: LS mean -1.33% [95% CI -1.43, -1.22]; ≥10 years: -1.24% [95% CI -1.35, -1.14]). Patients with baseline HbA1c ≥8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (≥8.5%: LS mean -1.86% [95% CI -1.97, -1.75]; <8.5%: LS mean -1.02% [95% CI -1.12, -0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75 mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c ≥8.5% than in those with <8.5%, except for the AWARD-4 study (combination with mealtime insulin). CONCLUSIONS: Across the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon-like peptide-1 receptor agonists.

DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity.

OBJECTIVE: Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). RESEARCH DESIGN AND METHODS: Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. RESULTS: We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. CONCLUSIONS: A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.

Variability in and predictors of glycaemic responses after 24 weeks of treatment with exenatide twice daily and exenatide once weekly.

The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily and once weekly were examined. Data were pooled from 8 exenatide-twice-daily and 5 exenatide-once-weekly studies. A baseline HbA1c-corrected measure of change in HbA1c after 24 weeks identified high, average and low responses. Multiple linear regression and multivariate generalized estimating equation models identified factors associated with high response. Among 2355 participants (exenatide twice daily, n = 1414; exenatide once weekly, n = 941), baseline HbA1c correlated with change in HbA1c (P < .0001). Across baseline HbA1c levels, the 25th to 75th percentile of HbA1c change ranged from -0.3% to -3.2% with exenatide twice daily and from -0.5% to -3.6% with exenatide once weekly. Asian ethnicity and older age were significantly associated with high response to exenatide twice daily; no factors were significantly associated with response to exenatide once weekly. These data provide clinically useful information for estimating the likelihood that, depending on baseline HbA1c, an individual can achieve HbA1c goals. The association between Asian ethnicity, age and high response to exenatide twice daily may relate to the specific effects of exenatide twice daily on postprandial glucose.

Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advances.

PURPOSE OF REVIEW: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are gastrointestinal peptides that play an important role as incretin hormones in the regulation of plasma glucose and insulin secretion. GLP-1-based therapies have therefore been implemented as treatment for type 2 diabetes (T2D). The purpose of this review is to summarize novel treatment options for T2D with GLP-1-based therapies. In addition, both peptides have relevant extrapancreatic effects that have been further characterized recently and are summarized in this review. RECENT FINDINGS: Novel findings regarding changes in GLP-1 secretion after bariatric surgery are highlighted, wherein GLP-1 plays a role in promoting body weight loss and diabetes remission. For T2D therapy, novel options with long-acting GLP-1 analogs are summarized that show a good efficacy and safety profile, also in combination with insulin as well as for obesity treatment. As GIP is not suitable for T2D therapy, extrapancreatic effects of GIP, mainly on bone metabolism that have been characterized recently, are described. These show that the activated GIP receptor is important to allow optimal bone mass and structure. SUMMARY: This review summarizes new findings on the physiology and pathophysiology of GLP-1 and GIP and novel therapeutic aspects.

Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study.

OBJECTIVE: The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated. RESULTS: Over 36 months, twice-daily exenatide was associated with improved body weight (-3.9 kg), waist circumference (-3.6 cm), systolic/diastolic BP (-2.5/-2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (-0.2 mmol/L), and hsCRP (-1.7 mg/L). Heart rate did not increase (-0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4%; P = 0.026) or lipid-lowering medication (8.4 vs 12.8%; P = 0.025). CONCLUSIONS: Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride. CLINICAL TRIAL REGISTRATION: NCT00359762, http://www.ClinicalTrials.gov.

Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial.

BACKGROUND: Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. METHODS: We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762. FINDINGS: We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. INTERPRETATION: These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. FUNDING: Eli Lilly and Company; Amylin Pharmaceuticals.

Anorexigenic effects of GLP-1 and its analogues.

GLP-1 receptors are expressed in the brain, especially in the regions responsible for the regulation of food intake, and intracerebroventricular injection of GLP-1 results in inhibition of food intake. Peripheral administration of GLP-1 dose-dependently enhances satiety and reduces food intake in normal and obese subjects as well as in type 2 diabetic patients. So far, the mechanisms by which GLP-1 exerts its effects are not completely clear. Interactions with neurons in the gastrointestinal tract or possibly direct access to the brain through the blood-brain barrier as observed in rats are possible and discussed in this chapter as well as a novel hypothesis based on the finding that GLP-1 is also expressed in taste cells. Finally, the role of GLP-1 receptor agonists as a possible treatment option in obesity is discussed as well as the role of GLP-1 in the effects of bariatric surgery on adiposity and glucose homeostasis.

Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus: current and emerging agents.

Novel therapeutic options for type 2 diabetes mellitus based on the action of the incretin hormone glucagon-like peptide (GLP)-1 were introduced in 2005. As injectable GLP-1 receptor agonists acting on the GLP-1 receptor, exenatide and liraglutide are available in many countries. In type 2 diabetes treatment, incretin-based therapies are attractive and more commonly used because of their mechanism of action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by these agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycaemia. Furthermore, GLP-1 receptor agonists allow weight loss and lower systolic blood pressure. This review gives a brief overview of the mechanism of action and summarizes the clinical data available on exenatide and liraglutide as established substances. It further highlights the clinical study data of exenatide once weekly as the first long-acting GLP-1 receptor agonist and covers other new long acting GLP-1 receptor agonists currently in clinical development. The placement of GLP-1 receptor agonists in the treatment algorithm of type 2 diabetes is discussed.

GLP-1 agonists and dipeptidyl-peptidase IV inhibitors.

Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In type 2 diabetes therapy, incretin-based therapies are attractive and more commonly used due to their action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by the above-mentioned agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycemias. GLP-1 receptor agonists allow weight loss; DPP-4 inhibitors are weight neutral. This review gives an overview on the mechanism of action and the substances and clinical data available.

Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia.

OBJECTIVE: Hypoglycemia causes recurrent morbidity in patients with type 2 diabetes. This study evaluated if exenatide twice daily (BID) was noninferior to premixed insulin aspart 70/30 BID (PIA) for glycemic control and associated with less hypoglycemia. RESEARCH DESIGN AND METHODS: In this open-label study, metformin-treated adults with type 2 diabetes were randomized to 26-week treatment with exenatide BID (4 weeks 5 µg, then 10 µg) or PIA. RESULTS: Exenatide BID (n = 181) was noninferior to PIA (n = 173) for A1C control (least squares [LS] mean change -1.0 vs. -1.14%; difference [95% CI] 0.14 [-0.003 to 0.291]) and associated with a lower risk for hypoglycemia (8.0 vs. 20.5%, P < 0.05). LS mean weight decreased by 4.1 kg and increased by 1.0 kg with PIA (P < 0.001). A total of 39.2 vs. 20.8% of patients reached the composite end point of A1C <7.0%, no weight gain, and no hypoglycemia (P < 0.001; post hoc analysis). CONCLUSIONS: In metformin-treated patients, exenatide BID was noninferior to PIA for glycemic control but superior for hypoglycemia and weight control.

Deteriorated executive functions in patients with successful surgery for pituitary adenomas compared with other chronically ill patients.

Pituitary adenomas, even after successful treatment, are associated with cognitive impairments. It is unclear whether these deficits are a consequence of unspecific factors associated with having a chronic illness and whether the cognitive dysfunctions exceed those of other chronically ill patients. Thirty-eight patients with transsphenoidal surgery for pituitary adenomas and 38 patients undergoing L-thyroxine replacement therapy after thyroid surgery were studied neuropsychologically with established tests. Executive function was examined with the Trail-Making Test A and B, working memory with the digit span test, attention with the digit symbol test, verbal memory with the German version of the Auditory Verbal Learning and Memory Test, and general verbal intelligence by a vocabulary test. Attention (p = .007), attentional speed (p = .0004), executive control (p = .04), and working memory (p = .01), were significantly reduced in patients with pituitary adenomas compared with other chronically ill patients. In contrast, no differences were found between the groups for verbal memory (all subtests: p ≥ .06). Patients with successful surgery for pituitary adenomas show also in comparison with other chronically ill patients an increased risk for deficits in certain aspects of cognitive function, including attention and working memory, supporting the relevance of the brain lesion and its treatment for these dysfunctions.

The evolving place of incretin-based therapies in type 2 diabetes.

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available.

Benefit-risk assessment of exenatide in the therapy of type 2 diabetes mellitus.

Exenatide is the first incretin mimetic, introduced into type 2 diabetes mellitus therapy in 2005, with first approval in the US. It is a glucagon-like peptide-1 (GLP-1) receptor agonist that can be used for treatment by twice-daily injection. A long-acting release formulation for once-weekly injection is in clinical development. Clinical studies and postmarketing experience with exenatide have shown a significant and sustained reduction in glycosylated haemoglobin (HbA(1c)) by approximately 1% together with other gylcaemic parameters without an intrinsic risk for hypoglycaemias, and a reduction in bodyweight by 5.3 kg in 82 weeks. Blood pressure and lipids are also favourably affected, but hard cardiovascular endpoints are not yet available. Animal studies show an improvement of beta-cell function and an increase in beta-cell mass after exenatide treatment. The most frequent adverse events associated with exenatide therapy are nausea and antibody formation (both approximately 40%). Nausea, mostly mild and transient, was responsible for a 6% dropout rate in clinical studies. A recent review on the association of acute pancreatitis with exenatide treatment showed no increased risk (relative risk 1.0; 95% CI 0.6, 1.7). This review gives a benefit-risk assessment of exenatide.