Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss.

New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.

Incretin and glucagon receptor polypharmacology in chronic kidney disease.

Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function. Additionally, these hormones and their pharmaceutical mimetics may have a direct impact on the kidney. Clinical studies have provided evidence that incretins, including those incorporating glucagon receptor agonism, are likely to exhibit improved kidney outcomes. Although further research is necessary, receptor polypharmacology holds promise for preserving kidney function through eliciting vasodilatory effects, influencing volume and electrolyte handling, and improving systemic risk factors.

Insulin sensitivity and beta cell function after Duodenal Mucosal Resurfacing (DMR): An Open-Label, Mechanistic, Pilot Study.

BACKGROUND AND AIMS: The duodenum has been shown to play a key role in glucose homeostasis. Duodenal mucosal resurfacing (DMR) is an endoscopic procedure for patients with type 2 diabetes (T2D) in which the duodenal mucosa is hydrothermally ablated. DMR improves glycemic control, but the underlying mechanisms remain unclear. Here, we report changes in glucoregulatory hormones and indices of insulin sensitivity and beta cell function after DMR. METHODS: We included 28 patients on non-insulin glucose lowering medications who underwent open-label DMR and a mixed meal test (MMT) in Revita-1 or Revita-2. Inclusion criteria were hemoglobin A1c (HbA1c) 7.6-10.4% and BMI 24-40kg/m2. Baseline and 3-months MMT data included plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations. Glucoregulatory hormones, insulin sensitivity indices (homeostatic model assessment for insulin resistance [HOMA-IR], Matsuda index [MI] and hepatic insulin resistance [HIR]), and beta cell function (insulinogenic index [IGI], disposition index [DI] and insulin secretion rate [ISR]) were assessed. RESULTS: Fasting insulin, glucagon, and C-peptide decreased significantly. Insulin sensitivity (HOMA-IR, MI, and HIR) and beta cell function (DI and ISR) all improved significantly. Decline in postprandial glucose, mainly driven by a decrease in fasting levels, was observed, as well as a decline in postprandial glucagon whereas GLP-1 and GIP did not change. CONCLUSIONS: Insulin sensitivity and insulin secretion improved 3 months after DMR. It is unlikely that incretin changes are responsible for improved glucose control after DMR. These data add to the growing evidence validating the duodenum as a therapeutic target for patients with T2D.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Metabolic traits affecting the relationship between liver fat and intrapancreatic fat: a mediation analysis.

AIMS/HYPOTHESIS: The clinical importance of fat deposition in the liver and pancreas is increasingly recognised. However, to what extent deposition of fat in these two depots is affected by intermediate variables is unknown. The aim of this work was to conduct a mediation analysis with a view to uncovering the metabolic traits that underlie the relationship between liver fat and intrapancreatic fat deposition (IPFD) and quantifying their effect. METHODS: All participants underwent MRI/magnetic resonance spectroscopy on the same 3.0 T scanner to determine liver fat and IPFD. IPFD of all participants was quantified manually by two independent raters in duplicate. A total of 16 metabolic traits (representing markers of glucose metabolism, incretins, lipid panel, liver enzymes, pancreatic hormones and their derivatives) were measured in blood. Mediation analysis was conducted, taking into account age, sex, ethnicity and BMI. Significance of mediation was tested by computing bias-corrected bootstrap CIs with 5000 repetitions. RESULTS: A total of 353 individuals were studied. Plasma glucose, HDL-cholesterol and triacylglycerol mediated 6.8%, 17.9% and 24.3%, respectively, of the association between liver fat and IPFD. Total cholesterol, LDL-cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, insulin, glucagon, amylin, C-peptide, HbA1c, glucagon-like peptide-1 and gastric inhibitory peptide did not mediate the association between liver fat and IPFD. CONCLUSIONS/INTERPRETATION: At least one-quarter of the association between liver fat and IPFD is mediated by specific blood biomarkers (triacylglycerol, HDL-cholesterol and glucose), after accounting for potential confounding by age, sex, ethnicity and BMI. This unveils the complexity of the association between the two fat depots and presents specific targets for intervention.

Incretins beyond type 2 diabetes.

Incretin-based therapies, in particular glucagon-like peptide-1 (GLP-1) receptor agonists, have been evaluated in other forms of diabetes, but randomised controlled trials are mainly limited to people living with type 1 diabetes. In this review we present the evidence issuing from these trials and discuss their clinical implications as well as the difficulties in interpreting the data. In type 1 diabetes, the addition of GLP-1 receptor agonists to intensive insulin therapy lowers weight and required insulin doses compared with placebo, but the effects on glucose control (HbA1c, risk of hypoglycaemia) are dependent on the different study protocols. Side effects are limited to the gastrointestinal complaints of nausea, vomiting and diarrhoea. We briefly discuss the potential for using GLP-1 receptor agonists as (adjunct) therapies in other forms of diabetes, where the evidence to date is scarce.

The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease.

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases.

Incretins and cardiovascular disease: to the heart of type 2 diabetes?

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes.

Dietary Vitamin A Affects the Function of Incretin-Producing Enteroendocrine Cells in Male Mice Fed a High-Fat Diet.

BACKGROUND: Retinol-binding protein 2 (RBP2) is an intracellular carrier for vitamin A in the absorptive enterocytes. Mice lacking RBP2 (Rbp2-/-) display an unexpected phenotype of obesity, glucose intolerance, and elevated glucose-dependent insulinotropic polypeptide (GIP) levels. GIP and glucagon-like peptide 1 (GLP-1) are incretin hormones secreted by enteroendocrine cells (EECs). We recently demonstrated the presence of RBP2 and other retinoid-related proteins in EECs. OBJECTIVES: Given RBP2's role in intracellular retinoid trafficking, we aimed to evaluate whether dietary vitamin A affects incretin-secreting cell function and gene expression. METHODS: Male Rbp2-/- mice and sex- and age-matched controls (n = 6-9) were fed a high-fat diet (HFD) for 18 wk containing normal (VAN, 4000 IU/kg of diet) or low (VAL, 25% of normal) vitamin A concentrations. Body weight was recorded biweekly. Plasma GIP and GLP-1 levels were obtained fasting and 30 min after an oral fat gavage at week 16. Glucose tolerance tests were also performed. Mice were killed at week 18, and blood and tissue samples were obtained. RESULTS: Rbp2-/- mice displayed greater weight gain on the VAN compared with the VAL diet from week 7 of the intervention (P ≤ 0.01). Stimulated GIP levels were elevated in Rbp2-/- mice compared with their controls fed the VAN diet (P = 0.02), whereas their GIP response was lower when fed the VAL diet (P = 0.03). Although no differences in GLP-1 levels were observed in the VAN diet group, a lower GLP-1 response was seen in Rbp2-/- mice fed the VAL diet (P = 0.02). Changes in incretin gene expression and that of other genes associated with EEC lineage and function were consistent with these observations. Circulating and hepatic retinoid levels revealed no systemic vitamin A deficiency across dietary groups. CONCLUSIONS: Our data support a role for RBP2 and dietary vitamin A in incretin secretion and gene expression in mice fed a HFD.

Maternal glucagon-like peptide-1 is positively associated with fetal growth in pregnancies complicated with obesity.

Pregnant women with obesity are more likely to deliver infants who are large for gestational age (LGA). LGA is associated with increased perinatal morbidity and risk of developing metabolic disease later in life. However, the mechanisms underpinning fetal overgrowth remain to be fully established. Here, we identified maternal, placental, and fetal factors that are associated with fetal overgrowth in pregnant women with obesity. Maternal and umbilical cord plasma and placentas were collected from women with obesity delivering infants who were LGA (n=30) or appropriate for gestational age (AGA, n=21) at term. Maternal and umbilical cord plasma analytes were measured using multiplex sandwich assay and ELISA. Insulin/mechanistic target of rapamycin (mTOR) signaling activity was determined in placental homogenates. Amino acid transporter activity was measured in isolated syncytiotrophoblast microvillous membrane (MVM) and basal membrane (BM). Glucagon-like peptide-1 receptor (GLP-1R) protein expression and signaling were measured in cultured primary human trophoblast (PHT) cells. Maternal plasma glucagon-like peptide-1 (GLP-1) was higher in LGA pregnancies and positively correlated to birthweight. Umbilical cord plasma insulin, C-peptide, and GLP-1 were increased in obese-large for gestational age (OB-LGA) infants. LGA placentas were larger but showed no change in insulin/mTOR signaling or amino acid transport activity. GLP-1R protein was expressed in the MVM isolated from human placenta. GLP-1R activation stimulated protein kinase alpha (PKA), extracellular signal-regulated kinase-1 and-2 (ERK1/2), and mTOR pathways in PHT cells. Our results suggest elevated maternal GLP-1 may drive fetal overgrowth in obese pregnant women. We speculate that maternal GLP-1 acts as a novel regulator of fetal growth by promoting placental growth and function.

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment.

AIMS: Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and polycystic ovarian syndrome (PCOS). Recently, gut hormones and their receptors have been identified in various reproductive organs indicating their potential regulatory effects on reproductive function. This review aims to give an overview of their potential effects. METHODS: This review focuses on literature that outlines modifications during obesity, diabetes and related infertility with an emphasis on gut hormones and their therapeutic potential. RESULTS: Evidence suggests that bariatric surgery has positive effects on fertility and PCOS where major alterations in metabolism occurs through restoration of gut hormone levels. This is thought to be due to the indirect effect weight loss and regulation of blood glucose has on the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axis influencing reproduction. CONCLUSIONS: Further research is required to elucidate the cellular mechanisms involved in the direct effects of gut hormone receptor activation on reproductive tissues. Current observations suggest a therapeutic role for gut hormones in infertility/PCOS associated with metabolic pathophysiology.

Pharmacological modulation of adaptive thermogenesis: new clues for obesity management?

BACKGROUND: Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment. PURPOSE: This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. ß3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Treating chronic kidney disease to reduce cardiovascular risk.

Chronic kidney disease (CKD) is a complex syndrome and a relevant problem of public health due to its large incidence and prevalence and to the high costs for its management. The hallmark of CKD, the progressive reduction in the glomerular filtration rate (eGFR), is strongly associated with an increase in cardiovascular events, such as fatal and non-fatal heart attack, stroke and heart failure, and mortality. Therefore, clinicians should pay any effort for preventing or slowing down the decline of renal function in order to reduce not only the occurrence of critical renal events (the need for dialysis or renal transplantation, among the most dreadful) but also the incidence of cardiovascular events. Accordingly, an early diagnosis and a targeted treatment in patients with kidney disease are crucial to reduce the evolution towards more advanced stages of the disease and the occurrence of complications. For a long time, the therapeutic approach to the majority of CKD patients was based on the strict control of risk factors, such as the diabetic disease and hypertension, together with the use of renin-angiotensin-aldosterone system inhibitors, particularly in the presence of albuminuria. Over time, this strategy proved to be only partially effective, since most CKD patients showed a progressive worsening of renal function. Gliflozins and incretins are novel anti-diabetic drugs that have been demonstrated to slow down the slope of eGFR reduction in patients with CKD, irrespective of diabetic status. Concurrently, these drugs showed to significantly impact cardiovascular prognosis reducing the incidence of clinical events. For their ability to act on a wide spectrum of disease, gliflozins and incretins are also called 'cardio-nephro-metabolic' drugs.

Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.

The role of cereal soluble fiber in the beneficial modulation of glycometabolic gastrointestinal hormones.

According to cohort studies, cereal fiber, and whole-grain products might decrease risk for type 2 diabetes (T2DM), inflammatory processes, cancer, and cardiovascular diseases. These associations, mainly affect insoluble, but not soluble cereal fiber. In intervention studies, soluble fiber elicit anti-hyperglycemic and anti-inflammatory short-term effects, partially explained by fermentation to short-chain fatty acids, which acutely counteract insulin resistance and inflammation. ß-glucans lower cholesterol levels and possibly reduce liver fat. Long-term benefits are not yet shown, maybe caused by T2DM heterogeneity, as insulin resistance and fatty liver disease - the glycometabolic points of action of soluble cereal fiber - are not present in every patient. Thus, only some patients might be susceptive to fiber. Also, incretin action in response to fiber could be a relevant factor for variable effects. Thus, this review aims to summarize the current knowledge from human studies on the impact of soluble cereal fiber on glycometabolic gastrointestinal hormones. Effects on GLP-1 appear to be highly contradictory, while these fibers might lower GIP and ghrelin, and increase PYY and CCK. Even though previous results of specific trials support a glycometabolic benefit of soluble fiber, larger acute, and long-term mechanistic studies are needed in order to corroborate the results.

Glucagon-like peptide-1 effect on ß-cell function varies according to diabetes remission status after Roux-en-Y gastric bypass.

AIMS: The contribution of endogenous glucagon-like peptide (GLP)-1 to ß-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on ß-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB. MATERIALS AND METHODS: Glucose, insulin secretion rates, ß-cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP-1 receptor blocker exendin9-39 (EX9). The cohort was retrospectively classified based on T2D remission (REM) status at the latest study time point: REM (n = 5), persistent T2D (n = 8), or impaired glucose tolerance (n = 16). RESULTS: EX9 blunted the increase in ß-cell glucose sensitivity at 3 months (-44.1%, p < .001) and 12 months (-43.3%, p < .001), but not at 24 months (-12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p < .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months. CONCLUSIONS: GLP-1 blockade reversed the improvement in ß-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.

Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: An adjusted indirect treatment comparison.

AIM: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. MATERIALS AND METHODS: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis. RESULTS: The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. CONCLUSIONS: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Discovery, synthesis and in combo studies of Schiff's bases as promising dipeptidyl peptidase-IV inhibitors.

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a-f and 9a-h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 µM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors.

The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study.

AIMS: The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and the interplay of peripheral artery disease (PAD) with therapy and amputation risk. METHODS AND RESULTS: Using Centricity Electronic Medical Records from USA, 3 293 983 patients with T2DM were identified: 169 739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149 826 received glucagon-like peptide 1 receptor agonists [GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure]; 448 225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1 954 353 received other ADDs. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000-08 and significantly increased to 12.3 in 2017. Over 17 211 719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins [95% confidence interval (CI) range: 1.06-1.67], and significantly higher in other groups (95% CI range: 1.96-2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA [hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05)], and lower in SGLT-2i vs. DPP-4i/other ADD [HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49)]. The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6-6.0). CONCLUSION: The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.