Search Results (19)

Background and Objectives: Obesity and type 2 diabetes (T2D) are closely linked and associated with a higher risk of complications. This study aims to evaluate the effectiveness of once-weekly semaglutide in achieving a composite endpoint of A1C and weight reduction. Materials and Methods: This retrospective cohort study assessed the effectiveness of semaglutide in obese patients with T2D at a tertiary care hospital in Saudi Arabia. This study included patients who received semaglutide treatment for 12 months, and the endpoint was reducing A1C by ≥ 1% and body weight by ≥ 5% after 12 months of starting semaglutide. Secondary endpoints include predictors of achieving the composite endpoint and the effect on the lipid profile. Results: The present study enrolled 459 participants, with dyslipidemia and hypertension being the most common comorbidities. After 12 months of treatment with semaglutide, 42% of the patients achieved the composite endpoint. Semaglutide significantly reduced weight, BMI, A1C, FBG, total cholesterol, LDL, and triglycerides. The subgroup analysis showed that patients who achieved the composite endpoint were younger and had significantly lower use of insulin. Females in the study had significantly higher BMI, A1C, and HDL levels and lower levels of triglycerides compared to males. Multivariate analysis revealed that baseline BMI (aOR = 0.953; 95% CI: 0.915 to 0.992; p = 0.02), baseline A1C (aOR = 1.213; 95% CI: 1.062 to 1.385; p = 0.004), and receiving insulin (aOR = 0.02; 95% CI: 0.001 to 0.343; p = 0.007) were significant predictors of composite endpoint achievement. Conclusions: Semaglutide is a valuable option for the treatment of obese patients with T2D. This study found that semaglutide is effective in reducing weight and A1C and improving the lipid profile. The predictors of achievement of the composite endpoint were lower baseline BMI, higher baseline A1C, and insulin non-use. Full article

Background/Objectives: Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is a well-established pharmacologic agent for inducing weight loss in individuals with obesity and is prescribed regardless of type 2 diabetes mellitus (DM) status. However, it remains unclear whether the weight-lowering efficacy of semaglutide differs significantly between individuals with and without DM. To address this question, we conducted a systematic review and meta-analysis comparing the effects of once-weekly subcutaneous semaglutide at 2.4 mg on weight loss in adults with and without DM. Methods: A comprehensive literature search was performed using the PubMed database to identify randomized controlled trials (RCTs) involving overweight or obese adults receiving semaglutide at 2.4 mg weekly for 40 to 70 weeks. Using a random-effects model, we estimated the weighted mean differences in body weight reduction between the two groups. Nine RCTs met the inclusion criteria, among which two provided subgroup data for participants with and without DM within the same trial population. Registration number in PROSPERO: CRD420251077610. Results: In participants with DM (n = 4 studies), semaglutide was associated with a weighted mean body weight reduction of −6.34% (95% confidence interval: −6.98 to −5.69), with negligible heterogeneity across studies (I² = 0.0%). By contrast, among participants without DM (n = 7 studies), the weighted estimate of weight loss was −11.57% (95% confidence interval: −12.94 to −10.19), with moderate heterogeneity observed (I² = 63.6%). Conclusions: The observed difference in weight loss efficacy between the groups was clinically meaningful. While once-weekly semaglutide at 2.4 mg elicited significant weight loss in both populations, the magnitude of effect was notably greater in those without DM. This disparity may be explained by metabolic characteristics frequently present in individuals with DM, such as insulin resistance, hyperinsulinemia, and compensatory mechanisms related to glycemic control. Full article

Background: Lipedema is a chronic disease of subcutaneous adipose tissue that predominantly affects women and is frequently associated with endocrinopathies such as insulin resistance and obesity. Its pathogenesis is still unclear, and treatment, which requires a multi-disciplinary approach, is prolonged over time and is not always effective. There is currently no drug treatment available for this disease. Methods: Five different cases of women with lipedema and insulin resistance, treated with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) and once-weekly exenatide, in association or not with lifestyle changes (diet or physical activity) for 3 to 6 months are described. Changes in anthropometric parameters, symptoms, clinical findings and the thickness of superficial adipose tissue measured by ultrasound were evaluated. Results: Treatment with exenatide, whether combined with a change in diet or physical activity, resulted in a reduction in the characteristic symptoms of lipedema, in pain evoked by pinching the adipose tissue fold and in the thickness of subcutaneous adipose tissue at the levels of the lower limbs, abdomen and upper limbs. In four out of five cases, a reduction in body weight was observed, particularly during the first three months of treatment and in cases with greater metabolic impairment. Clinical, instrumental and subjective improvements were also observed in cases where there was no reduction in body weight and in patients who had previously undergone lower limb liposuction. Conclusions: The improvement in symptoms and clinical signs of lipedema, in addition to the reduction in adipose tissue in patients with lipedema and insulin resistance with exenatide, suggests a novel pharmacological approach to the disease, which can be combined with other conservative and surgical treatments to promote weight reduction. These results also highlight the association of this disease with metabolic alterations and the fundamental role of an accurate diagnosis followed by the treatment of comorbidities and excess weight in these patients. Full article

Background: Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist administered subcutaneously once a week, developed through recombinant DNA technology, and prescribed as an add-on to diet and exercise for managing type 2 diabetes mellitus in adults. In several clinical trials, once-weekly dulaglutide has demonstrated reductions in cardiovascular risk associated with diabetes, as well as improvements in glycemic control and weight reduction. The scope of this study was to evaluate the effect of dulaglutide 1.5 mg on glycemic control, weight management, and LDL-cholesterol levels in patients with uncontrolled type 2 diabetes mellitus. Methods: We retrospectively reviewed the medical records of 55 patients with inadequately controlled type 2 diabetes mellitus who were on oral antidiabetic agents and insulin, and who were additionally treated with dulaglutide 1.5 mg. We monitored fasting plasma glucose and glycated hemoglobin (HbA1c) at baseline and at 6, 12, and 24 months after initiating dulaglutide treatment. Weight, body mass index, and LDL-cholesterol were assessed at baseline and after 24 months of dulaglutide therapy. Results: Treatment with dulaglutide resulted in significant improvements in fasting plasma glucose and HbA1c after 6 months (p < 0.001), 12 months (p < 0.001), and 24 months (p < 0.001). A significant weight reduction was observed after 24 months of dulaglutide therapy (−3.3 kg; p < 0.001). In addition, we observed a significant reduction in LDL-cholesterol after 24 months (p < 0.001). Conclusions: Our data demonstrate that dulaglutide 1.5 mg significantly improves glycemic control, reduces body weight, and lowers LDL-cholesterol in Romanian patients with inadequately controlled type 2 diabetes. Full article

The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer’s disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes. Full article

The last two decades have provided far more options f both patients and their physicians in the treatment of diabetes mellitus. While dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been approved for nearly two decades, sodium–glucose cotransporter 2 inhibitors (SGLT-2is) are relatively new. Of interest to perioperative physicians, these drugs present specific perioperative concerns, prompting many societies to issue guidelines. Retained gastric contents due to slow gastric emptying is a significant drawback of GLP-1RAs, increasing the risk of aspiration. Recommendations include withholding GLP-1RAs for a predefined period of time, performing gastric ultrasound to evaluate gastric contents, modifying anesthesia management, particularly with regard to the airway, or canceling the scheduled (elective) surgery or procedure. SGLT-2is are known to increase the risk of euglycemic ketoacidosis. The benefits of both GLP-1RAs and SGLT-2is extend beyond the treatment of diabetes. As a result, perioperative physicians may encounter their use outside of their traditional indications. SGLT-2is are being used extensively to treat heart failure and obesity, for example. There have been other developments as well. For instance, Imeglimin, a variant of metformin available in Japan and India, Icodec, a once-weekly basal insulin formulation, and IcoSema, a once-weekly combination of Icodec plus semaglutide, are all being explored, although in their early stages or facing approval challenges. Full article

Background: Diabetes mellitus (DM) significantly impacts global health due to its complications and the economic burden it places on healthcare systems. The rise of novel once-weekly diabetes medications with different mechanisms of action necessitates an evaluation of their relative efficacy and safety. Objectives: This study compares the efficacy and tolerability of once-weekly insulin analogs (icodec and BIF) with once-weekly GLP-1/GIP agonists (semaglutide, exenatide, tirzepatide, dulaglutide) in managing type 2 diabetes mellitus (T2DM). Methods: We conducted a network meta-analysis (NMA) using data from randomized controlled trials (RCTs) that compared these treatments with a baseline of daily basal insulin. Primary outcomes included changes in HbA1c, body weight, and tolerability. Results: The analysis integrated data from 25 RCTs, involving 18,257 patients. Tirzepatide significantly outperformed other treatments in reducing HbA1c and promoting weight loss. Weekly insulins, compared to GLP-1/GIP agonists, showed a more tolerable profile and were beneficial for certain patient demographics emphasizing weight stability. Conclusion: Our findings suggest that while once-weekly GLP-1/GIP agonists provide superior glycemic control and weight management, weekly insulins offer viable options for patients prioritizing fewer side effects and weight stability. This comprehensive comparison aids in refining personalized treatment strategies for T2DM management. Full article

Background. One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). Methods. PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. Results. The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of −0.14% [95%CI −0.25; −0.03], p = 0.01, and I² 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I² 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I² 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of −0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (−5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). Conclusion. Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients’ education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680. Full article

Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient’s circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec’s efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (>180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management. Full article

Diabetes mellitus (DM) is a chronic metabolic disease affecting over 500 million people worldwide, which leads to severe complications and to millions of deaths yearly. When therapeutic goals are not reached with diet, physical activity, or non-insulin drugs, starting/adding insulin treatment is recommended by international guidelines. A novel recombinant insulin is icodec, a once-weekly insulin that successfully completed phase III trials and that has recently obtained the marketing authorization approval from the European Medicines Agency. This narrative review aims to assess icodec pharmacological and clinical features concerning evidence on benefit–risk profile, as compared to other basal insulins, addressing the potential impact on patients’ unmet needs. Icodec is a full agonist, recombinant human insulin analogue characterized by an ultra-long half-life (196 h), enabling its use in once-weekly administration. Phase III randomized clinical trials involving more than 4000 diabetic patients, mostly type 2 DM, documented non-inferiority of icodec, as compared to currently available basal insulins, in terms of estimated mean reduction of glycated hemoglobin levels; a superiority of icodec, compared to control, was confirmed in insulin-naïve patients (ONWARDS 1, 3, and 5), and in patients previously treated with basal insulin (ONWARDS 2). Icodec safety profile was comparable to the currently available basal insulins. Once-weekly icodec has the potential to improve patients’ adherence, thus positively influencing patients’ treatment satisfaction as well as quality of life, especially in type 2 DM insulin-naïve patients. An improved adherence might positively influence glycemic target achievement, reduce overall healthcare costs and overcome some of the unmet patients’ needs. Icodec has the potential to emerge as a landmark achievement in the evolution of insulin therapy, with a positive impact also for the National Health Services and the whole society. Full article

Growth hormone treatment has effectively restored normal growth in children with growth hormone deficiency (GHD); however, it poses challenges in compliance with a daily growth hormone injection regimen, leading to low adherence and persistence rates. Once-weekly Somapacitan is a potential alternative for treating children with GHD. This study aimed to evaluate the efficacy, safety, and adherence of once-weekly subcutaneous Somapacitan compared to daily growth hormone injection in prepubertal children with GHD. A search for the published records was carried out on 17 October 2023 utilizing the searching feature available on PubMed, Embase, and Scopus. Primary study outcomes included (1) efficacy, measured by height velocity (HV), standard deviation score (SDs), height SDs, insulin-like growth factor-SDs (IGF-I SDs), and bone age vs. chronological age ratio (BA vs. CA); (2) safety, assessed through adverse events and injection site reactions; and (3) adherence, determined by the percentage of the sample completing treatments. Secondary outcomes evaluated disease burden scores, divided into three subgroup domains: emotional well-being, physical functional, and social well-being scores. We retrieved 6 studies that were eligible for the systematic review (417 versus 186 for intervention and control, respectively). Only 2 of the total included studies were eligible for pooled analysis (175 versus 82 for intervention and control, respectively). The efficacy profile of Somapacitan was similar to daily growth hormones, indicated by HV (mean difference (MD = 0.04; p = 0.96), HV SDs (MD = −0.71; p = 0.09), height SDs (MD = 0.11; p = 0.69), IGF-I SDs (MD = 0.06; p = 0.70), and CA vs. BA (MD = 0.67; p = 0.70)), demonstrated similar and non-inferior outcomes. Treatment adherence is 3 times higher in the Somapacitan group as compared to control (OR = 3.02; p = 0.03) with adherence rates reaching 95% and 88% for Somapacitan and Norditropin^®, respectively. The disease burden measurement is similar in Somapacitan and daily growth hormones (MD = −0.62; p = 0.83), as indicated by the Growth Hormone Deficiency–Child Impact Measure. In almost all outcomes, the level of confidence is strong. The confidence level in the data is generally strong, but for CA vs. BA and the subgroup of severe adverse events with heterogeneity >50%, the confidence level is moderate. Although the efficacy and safety profiles of Somapacitan were found to be similar to those of daily growth hormones, a reduced frequency of once-weekly Somapacitan injections led to increased adherence. PROSPERO registration: CRD42023473209. Full article

Background: The number of people with type 2 diabetes is increasing daily, and therefore, effective therapy is needed to successfully regulate glycemia and reduce the risk of associated complications. Recently, an oral formulation of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has become available. Therefore, the aim of our study was to compare the effectiveness of the new oral formulation and the existing injectable formulation of semaglutide in terms of glycemic and body weight control in a real-world setting. Patients and methods: This was a single-center retrospective observational study conducted at the Rijeka Clinical Hospital Centre. A total of 106 patients with inadequately controlled type 2 diabetes (HbA1c ≥ 7%) on different oral or basal insulin supported oral therapy were enrolled in the study, and data from electronic medical records were retrospectively collected and analyzed from May 2021 to November 2022. All subjects were GLP-1 RA-naive and consequently prescribed 0.5 or 1.0 mg of once weekly injectable semaglutide (IS) or 7 mg or 14 mg of once daily oral semaglutide (OS) for at least 6 months. Glycated hemoglobin (HbA1c), body weight, and body mass index (BMI) were assessed prior to semaglutide administration and after a 6-month follow-up period. The primary endpoint was the change from baseline in HbA1c, and secondary endpoints were the change in body weight and the proportion of participants with a reduction in body weight of ≥5% and ≥10%, respectively, 6 months after the initiation of semaglutide treatment. Results: At the 6-month follow-up, no significant difference was observed between the two formulations in terms of HbA1c reduction (IS −1.1% vs. OS −1.4%, p = 0.126) and weight loss (IS −6.50 kg vs. OS −5.90 kg, p = 0.714). Exactly the same proportion of participants in both groups achieved a weight loss of ≥5% (56.7%, n = 30). A weight loss ≥ 10% was observed in 20.7% (n = 11) of participants administered IS and 15.1% (n = 8) of participants administered OS, respectively (p = 0.454). Conclusion: In a real-world setting, oral semaglutide as an add-on therapy to ongoing antihyperglycemic treatment in patients with inadequately controlled type 2 diabetes who had not previously received GLP-1 RA demonstrated a similar effectiveness as injectable semaglutide in terms of glycemic control and weight loss after 6 months of treatment. Full article

Background: Tirzepatide (TZP) is a once-weekly glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic-polypeptide (GIP) receptor co-agonist approved for T2D. TZP provides promising evidence in improving glucose control and weight loss in T2D and obesity across preclinical and human studies, including data from the SURPASS program. Aims: The goal of this paper was to review the evidence on TZP in terms of glucose control, body weight, and the progression of chronic diabetes-related complications and comorbidities. Results: The mean change in HbA1c ranged from −1.6% to −2.06% over placebo, from −0.29% to −0.92% over each GLP-1RAs, and from −0.7% to −1.09% over basal insulins. In SURPASS-6, TZP was more effective than insulin lispro U100 added to basal insulin in reducing HbA_1c levels at the study end (−2.1% vs. −1.1%, respectively). Compared to placebo, TZP induces a significant weight loss: 7.5 (5 mg/week); 11 (10 mg/week); and 12 kg (15 mg/week). Compared to GLP-1RAs, TZP reduces body weight from −1.68 kg to −7.16 kg depending on the dose (5 to 15 mg, respectively). Compared to basal insulin alone rigorously titrated, TZP added onto basal-insulin results in the best strategy for the composite endpoint of improvement of glucose control and weight loss. In SURPASS-6, TZP compared to insulin lispro U100 in add-on to insulin glargine U100 reduced body weight by 9 kg in mean (versus weight gain in basal-bolus users: +3.2 kg). TZP has pleiotropic effects potentially dampening the individual cardiovascular risk, including a reduction in systolic arterial pressure by 4 to 6 mmHg and total cholesterol by 4–6% compared to baseline. A post hoc analysis of SURPASS-4 revealed that TZP, compared to glargine U100, delayed the rate of glomerular filtration decline (−1.4 mL/min vs. −3.6 mL/min, respectively), reduced the rate of urinary albumin excretion (−6.8% vs. +36.9%, respectively), and was associated with a lower occurrence of the composite renal endpoint (HR 0.58 [0.43; 0.80]). Conclusions: Consistent evidence indicates that TZP dramatically changes the clinical course of T2D in different clinical scenarios. The efficacy and safety of TZP on chronic diabetes-related comorbidities and complications seem promising, but ongoing trials will clarify the real benefits. Full article

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities. Full article

The global prevalence of comorbid diabetes and frailty is increasing due to increasing life expectancy. Frailty appears to be a metabolically heterogeneous condition that may affect the clinical decision making on the most appropriate glycaemic target and the choice of the most suitable hypoglycaemic agent for each individual. The metabolic profile of frailty appears to span across a spectrum that starts at an anorexic malnourished (AM) frail phenotype on one end and a sarcopenic obese (SO) phenotype on the other. The AM phenotype is characterised by significant weight loss and less insulin resistance compared with the SO phenotype, which is characterised by significant obesity and increased insulin resistance. Therefore, due to weight loss, insulin therapy may be considered as an early option in the AM frail phenotype. Insulin-related weight gain and the anabolic properties of insulin may be an advantage to this anorexic phenotype. There is emerging evidence to support the idea that insulin may improve the muscle function of older people with diabetes, although this evidence still needs further confirmation in future large-scale prospective studies. Long acting insulin analogues have a lower risk of hypoglycaemia, comapred to intermediate acting insulins. Additionally their simple once daily regimen makes it more appropriate in frail older patients. Future research on the availability of new once-weekly insulin analogues is appealing. The goals of therapy are to achieve relaxed targets, avoid hypoglycaemia and to focus on the maintenance of quality of life in these vulnerable patients. Full article