Die Praxisempfehlungen der Deutschen Diabetes Gesellschaft (DDG) zusammen mit der Deutschen Gesellschaft für Innere Medizin (DGIM) lehnen sich eng an die Inhalte der Nationalen VersorgungsLeitlinie (NVL) "Therapie des Typ-2-Diabetes" an. Die in diesen Praxisempfehlungen abgebildeten Inhalte sind zum großen Teil die konsentierten Abschnitte der ganzen Arbeitsgruppe, die für die Erarbeitung der Nationalen VersorgungsLeitlinie verantwortlich war. Umfangreiche Details einschließlich der wissenschaftlichen Belege finden Sie in der Langfassung der NVL (http://www.versorgungsleitlinien.de).

Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide 1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.

Individuals with type 2 diabetes are at high risk of postprandial falls in blood pressure (BP) (i.e., a reduction in systolic BP of ³20mmHg, termed postprandial hypotension (PPH)), which increases the risk of falls and mortality. This study evaluated the effects of oral metformin on postprandial BP, heart rate (HR), glucagon-like peptide-1 (GLP-1) and gastric emptying (GE) in individuals with type 2 diabetes. We studied 16 subjects (5 female) before and after ingestion of a 75g radiolabeled glucose drink, after both acute (30 min) and subacute (b.i.d for 7 days) administration of metformin (850mg) or placebo, in a double-blind, randomized, crossover design. 24-hour ambulatory BP measurement following standardized meals (breakfast, lunch and dinner) was used to quantify PPH events. The primary outcome was the postprandial fall in systolic BP. We found that acute administration of metformin did not affect BP, HR, plasma insulin or GLP-1 levels, but slowed GE (P<0.001) and reduced the glycemic response to oral glucose (P<0.001). Sub-acute metformin reduced PPH events by 32% (P=0.035), in association with an increase in HR (P=0.029), slowing of GE (P<0.001), augmentation of plasma GLP-1 (P<0.001), and a reduction in plasma glucose (P<0.001) without affecting plasma insulin. Pre-prandial BP was unaffected by metformin. To conclude, in type 2 diabetes oral metformin attenuates the hypotensive response to meals, associated with stimulation of GLP-1 and slowing of GE to reduce PPH.

Die Inkretinhormone „glucose-dependent insulinotropic peptide“ (GIP) und „glucagon-like peptide 1“ (GLP-1) werden nach oraler Zufuhr von Nährstoffen von enteroendokrinen Zellen der Darmschleimhaut sezerniert und stimulieren in Abhängigkeit von der Blutzuckerkonzentration die Insulinsekretion. Bei Gesunden sind sie zusammen für etwa 63–74

Einleitung, Fragestellung. Der Inkretin-Effekt ist bei Typ 2 Diabetes (T2D) und Chronischer Pankreatitis mit Diabetes mellitus (CPD) reduziert, obwohl die Inkretinhormone Glucose-dependent Insulinotropic Polypeptide (GIP) und Glucagon-like Peptide-1 (GLP-1) unbeeinträchtigt sezerniert werden. Wir wollten untersuchen, ob die Erklärung darin liegt, dass die Rezeptoren für GIP und GLP-1 in endokrinen Inseln/ß-Zellen bei T2D und/oder CPD vermindert exprimiert werden.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GLP-1- and glucose-dependent insulinotropic polypeptide receptor co-agonist tirzepatide (referred to here collectively as "GLP-1-based therapy") are incretin-based therapies being used increasingly in the management of both type 2 diabetes and obesity. They are now recognized to have beneficial effects beyond improved glycemic control and weight loss, including cardiovascular and renal protection. GLP-1-based therapy also slows gastric emptying, which has benefits (lowering postprandial glucose), but also potential risks (eg, hypoglycemia in individuals on insulin or sulphonylurea therapy). Their effects on the gallbladder may also be beneficial, contributing to reducing postprandial triglycerides, but they also potentially increase the risk of biliary disease. In this review, we summarize the effects of GLP-1 and incretin-based therapeutics on gastric, biliary and small intestinal function. An improved understanding of these effects will optimize the use of these drugs.

Background: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial.Methods: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged >= 40 years, with established atherosclerotic CV disease, HbA1c >= 7% to <= 10.5%, and body mass index >= 25 kg/m(2) were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until >= 1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis).Results: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m(2). Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing.Conclusion: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.

Introduction & Objective: Statistical and mechanistic evidence suggest that sodium-glucose co-transporter 2 inhibitors (SGLT2i)-induced change in haematocrit may affect cardiovascular risk. Since the magnitude of change is variable but manifested early, we explored whether the within 6-month changes in haematocrit in subjects initiated with SGLT2i could help identify those who would benefit most in terms of cardiovascular risk reduction. Methods: Using real-world data in GPRD GOLD and Aurum, a series of open cohort studies were performed in individuals with diabetes mellitus type 2 (T2DM). Primary outcome was composite end-point including all-cause mortality, myocardial infarction ischaemic heart disease and stroke. Based on linearity analyses and clinical interpretability, individuals were categorised into three subgroups of the observed absolute haematocrit change (“negative”, “positive” = 0-4, “highly positive”=>4). Primary analysis was conducted with competing cox proportional hazard model with restricted cubic spline. Results: A total of 37,2336 individuals, over 40 years-old, with T2DM under treatment with SGLT2i were included and followed for ~2.4 years with a total observation worth of ~86000 person-years. The subgroup with the negative haematocrit change was found to be at a significantly increased risk of manifesting the composite outcome [adjusted hazard ratio and 95% confidence intervals, aHR (95% CI): 1.23 (1.12, 1.36)], death from any cause [1.33 (1.19,1.49]) and heart failure [1.35 (1.14, 1.60)], compared to the reference group. 0-9.83%). Sensitivity analyses did not alter the findings. Conclusion: Among individuals with T2DM at low baseline risk of cardiovascular disease, an early increase in haematocrit after SGLT2i institution may be regarded as an indicator of future cardiovascular benefit. Disclosure K.A. Toulis: None. J. Wang: None. L. Tan: None. K. Nirantharakumar: Consultant; Boehringer-Ingelheim. Research Support; GlaxoSmithKline plc. M.A. Nauck: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Merck & Co., Inc. Speaker's Bureau; Merck & Co., Inc. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk, Medscape. Advisory Panel; Pfizer Inc., Structure Therapeutics, Inc., Sun Pharmaceutical Industries Ltd. Speaker's Bureau; Medical Learning Institute, Medfyle. Advisory Panel; Regor. Other Relationship; Inventiva Pharma. Funding EFSD Future Leaders Mentorship Programme for Clinical Diabetologists (supported by an unrestricted educational grant from AstraZeneca)

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.

Fragestellung Ziel der vorliegenden Arbeit war es, die Effektivität, Sicherheit und Verträglichkeit von injizierbaren, Inkretin-basierten Glukose-senkenden Medikamenten (incretin-based glucose-lowering medications; IBGLM) im Vergleich zu einer Basalinsulintherapie bei Menschen mit Typ 2 Diabetes (T2DM) zu untersuchen.

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 (HbA(1c)) 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, HbA(1c) 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 HbA(1c) by 0.48 (0.45-0.52)% more than did basal insulin treatment. This effect was driven by pooled long-acting GLP-1RAs (Delta HbA(1c) -0.25 [-0.38; -0.11]%) and the only GIP/GLP-1 receptor co-agonist, tirzepatide (pooled doses; Delta HbA(1c) -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.