Explore the vast range of titles available.

Abstract The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.More than 7,000 clinical trials are currently ongoing involving new drugs for type 2 diabetes mellitus (T2DM). This Review summarizes the novel drugs in development for T2DM that improve insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and newer incretin-based co-agonists have transformed obesity and type 2 diabetes (T2D) management, achieving unprecedented weight loss and cardiometabolic benefits. However, their effects on body composition, particularly lean and skeletal muscle mass, remain incompletely defined. In this current review, we examined the influence of GLP-1 RAs and incretin hormone agonists on lean tissue, integrating physiological, clinical, and mechanistic perspectives. We first outlined the physiology of incretin hormones, with emphasis on their metabolic roles and potential relevance to muscle health. We then discussed sarcopenia and sarcopenic obesity as conditions of rising clinical concern, given their overlap with obesity and metabolic disease. Evidence from preclinical studies and randomized clinical trials indicates that while GLP-1-based therapies predominantly reduce adipose tissue, including visceral and ectopic depots, but they also produce absolute reductions in lean mass, generally representing 20–30% of total weight loss. The extent to which these changes translate into impaired muscle function or increased vulnerability to frailty remains unclear. Preservation of lean and skeletal muscle mass is a critical yet underexplored aspect of incretin-based weight loss. Current studies are constrained by methodological heterogeneity, small sample sizes, and limited assessment of functional outcomes. Data on dual and triple agonists are emerging but remain limited. Future research should integrate standardized body-composition measures, mechanistic exploration, and adjunctive interventions such as resistance training or protein optimization.

Aims/hypothesis The aim of this study was to assess the dose–response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA 1c levels and bodyweight reduction. Methods This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18–75 years with type 2 diabetes, an HbA 1c level of 53–86 mmol/mol (7.0–10.0%) and a BMI of 25–50 kg/m 2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1–4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA 1c after 16 weeks’ treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks’ treatment. Results A total of 413 participants were randomised (DG1, n =50; DG2, n =50; DG3, n =52; DG4, n =50; DG5, n =51; DG6, n =50; semaglutide, n =50; placebo, n =60). The full analysis set comprised 411 treated participants (DG6, n =49; placebo, n =59). Adjusted mean (95% CI) HbA 1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks’ treatment: DG1 ( n =41), −9.92 mmol/mol (−12.27, −7.56; −0.91% [−1.12, −0.69]); DG2 ( n =46), −15.95 mmol/mol (−18.27, −13.63; −1.46% [−1.67, −1.25]); DG3 ( n =36), −18.72 mmol/mol (−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 ( n =33), −17.01 mmol/mol (−19.59, −14.43; −1.56% [−1.79, −1.32]); DG5 ( n =44), −17.84 mmol/mol (−20.18, −15.51; −1.63% [−1.85, −1.42]); DG6 ( n =36), −18.38 mmol/mol (−20.90, −15.87; −1.68% [−1.91, −1.45]). The mean reduction in HbA 1c was similar with low-dose survodutide (DG2: −15.95 mmol/mol [−1.46%]; n =46) and semaglutide (−16.07 mmol/mol [−1.47%]; n =45). Mean (95% CI) bodyweight decreased dose-dependently up to −8.7% (−10.1, −7.3; DG6, n =37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (−5.3% [−6.6, −4.1]; n =45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. Conclusions/interpretation Survodutide reduced HbA 1c levels and bodyweight after 16 weeks’ treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. Trial registration ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. Funding Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Graphical Abstract

Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs.

Differential Antidiabetic Efficacy of Incretin Agonists Versus DPP-4 Inhibition in High Fat–Fed Mice Benjamin J. Lamont and Daniel J. Drucker From the Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Address correspondence and reprint requests to Dr. Daniel J. Drucker, Mt. Sinai Hospital, 600 University Ave., SLRI975C, Toronto, ON, Canada M5G 1X5. E-mail: d.drucker{at}utoronto.ca Abstract OBJECTIVE— We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist d -Ala 2 -GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable antidiabetic actions in high fat–fed mice. RESEARCH DESIGN AND METHODS— High fat–fed mice were administered twice-daily injections of Ex-4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP-4i) in food to produce sustained inhibition of DPP-4 activity. RESULTS AND CONCLUSIONS— Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP-4i prevented weight gain. Although Ex-4 improved oral glucose tolerance and insulin-to-glucose ratios after an intraperitoneal glucose tolerance test (IPGTT), DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after an oral glucose tolerance test. The extent of improvement in glycemic control was more sustained with continuous DPP-4 inhibition, as evidenced by loss of glucose control evident 9 h after peptide administration and a significant reduction in A1C observed with DPP-4i but not with DA-GIP or Ex-4 therapy. DA-GIP, but not Ex-4 or DPP-4i, was associated with impairment in insulin sensitivity and increased levels of plasma leptin and resistin. Although none of the therapies increased β-cell mass, only Ex-4–treated mice exhibited increased pancreatic mRNA transcripts for Irs2 , Egfr , and Gck . These findings highlight significant differences between pharmacological administration of incretin receptor agonists and potentiation of endogenous GLP-1 and GIP via DPP-4 inhibition. AUC, area under the glucose curve DA-GIP, d-Ala2-glucose-dependent insulinotropic polypeptide DPP-4, dipeptidyl peptidase-4 DPP-4i, dipeptidyl peptidase-4 inhibitor Ex-4, exendin-4 GIP, glucose-dependent insulinotropic polypeptide GLP-1, glucagon-like peptide 1 GLP-1R, glucagon-like peptide 1 receptor IPGTT, intraperitoneal glucose tolerance test ITT, insulin tolerance test KIU, kallikrein inhibitor unit MCP-1, monocyte chemoattractant protein-1 OGTT, oral glucose tolerance test PAI-1, plasminogen activator inhibitor 1 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 10 October 2007. DOI: 10.2337/db07-1202. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 1, 2007. Received August 24, 2007. DIABETES

Incretin effect enhancers are drugs used in the treatment of Type 2 diabetes and include GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors (gliptins). Variants in several genes were shown to be involved in the physiology of incretin secretion. Only two gene variants have evidence also from pharmacogenetic studies. rs7903146 C>T and rs7202877 T>G minor allele carriers were both associated with a smaller reduction in HbA1c after gliptin treatment when compared with major allele carriers. After replication in further studies, these observations could be of clinical significance in helping to identify patients with potentially lower or higher response to gliptin treatment.

Hypertension is a frequent comorbidity of obesity that significantly and independently increases the risk of cardiovascular and renal events. Obesity-related hypertension is a major challenge to the healthcare system because of the rapid increase in obesity prevalence worldwide. However, its treatment is still not specifically addressed by current guidelines. Weight loss (WL) per se reduces blood pressure (BP) and increases patient responsiveness to BP-lowering medications. Thus, a weight-centric approach is essential for the treatment of obesity-related hypertension. Diet and physical activity are key components of lifestyle interventions for obesity-related hypertension, but, in real life, their efficacy is limited by poor long-term patient adherence and frequently require pharmacotherapy implementation to achieve target BP. In this context, first-generation anti-obesity drugs such as orlistat, phentermine/topiramate, and naltrexone/bupropion are poorly effective, whereas second-generation incretin receptor agonists, including the GLP-1 receptor agonists liraglutide and semaglutide, and in particular the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) co-agonist tirzepatide, substantially contribute to effective WL and BP control in obesity. SGLT2 inhibitors are weak body weight and BP-lowering medications, but clearly synergize the benefits of these medications. Bariatric surgery remains the gold standard treatment for severe “pathological” obesity and related life-threatening complications. Renal denervation is a valuable rescue treatment for drug-resistant hypertension, commonly related to obesity. Integrating a multifaceted weight-based approach with other strategies, such as antihypertensive drugs and renal denervation, could specifically target the main neuro-hormonal and renal pathophysiological mechanisms of obesity-related hypertension, including sympathetic-nervous and renin–angiotensin–aldosterone systems overactivity, salt retention, and volume expansion. This comprehensive strategy can provide a personalized algorithm for managing hypertension in obesity within the context of “precision medicine” principles.

Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer’s disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.