In this randomized, double-blind, double-dummy, phase 2 trial, the efficacy and safety of once-weekly treatment with the basal insulin analogue icodec were compared with those of once-daily insulin ...glargine U100 in patients with type 2 diabetes who had not taken insulin. Once-weekly icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily glargine.
Obesity treatment based on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) proved to limit morbidity and mortality in adult population. In children, optimizing lifestyle intervention (LSI) and ...reducing culpable environmental exposures represent the mainstay strategy for obesity prevention and management. However, there remains a subset of children and adolescents whose obesity is resistant to lifestyle approach. For these poor responders, the need for safe and effective weight-reducing agents is apparent. The purpose of this review is to provide an overview of the efficacy and safety of approved GLP-1 RA in the management of adult and pediatric obesity.
We presented the main outcomes of clinical trial programs called SCALE and STEP that supported a market authorization approval for liraglutide and semaglutide for the treatment of obesity in adult population. Then, we summarized the studies on the efficacy of GLP-1 RA in pediatric obesity that have been accumulating from 2 larger studies with liraglutide and few other smaller studies with exenatide and liraglutide. The results indicate that GLP-1 RA is safe, tolerable, and effective in reducing weight and also in improving cardiometabolic profile in children with obesity and poor response to LSI alone. At present, liraglutide is the first and so far the only GLP-1 RA that received FDA approval in 2020 for use in children aged 12-17 years with obesity. New trials including semaglutide for pediatric obesity are ongoing.
There is a strong interest in current use and further development of obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism. In adolescents with obesity, who are poor responders to lifestyle approach, the use of GLP-1 RA as an adjunct to LSI is effective and safe. Due to limited experience, a general recommendation is to prioritize long acting over short acting GLP-1 RA because they are approved for the treatment of obesity and have better tolerability, safety, and treatment response effect. In the future research, more high-grade evidence including novel iterations of GLP-1 agonism and long-term follow-ups are needed in pediatric population.
Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a ...well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.
The proportion of subjects who lost ≥5 % of baseline body weight with semaglutide was 68.8 %.7 The difference between efficacy regarding weight loss in studies conduced with participants without ...diabetes and that with diabetes was expected since the coexistence of diabetes has been consistently related with less weight loss for all AOM.8 Moreover, the design of STEP clinical programme was not well-balanced regarding sex.9 While the STEP 2 trail included 51 % female participants,7 the STEP 1, STEP 3 and STEP 4 trials included 73 %, 81 %, and 79 % female participants.4–6 Thus STEP 2, has the greatest proportion of men (49.1 %) than the other trials (19.0–25.9 %). Cumulative evidence suggests sexual dimorphic response with GLP-1 RAs regarding the weight loss.10 In a retrospective study with exenatide, women lost 7.0 kg compared to 3.3 kg in men.11 Similar results were presented in a cohort study, in which 33 % of women treated with exenatide achieved weight loss targets compared to 17 % of men.12 Studies that used different representatives of the class, such as dulaglutide and liraglutide, have generated similar findings.13,14 One reason for intersex difference is presumably related to exposure difference due to female lower average body weight.14 In addition, a pharmacokinetics analysis showed that liraglutide exposure was 32 % higher in women than in men of comparable weight, thus identifying the female sex as weight independent predictor of exposure difference.15 Weight loss increased with greater exposure to GLP-1 RAs and appeared to level off at the highest exposures in most female individuals. In case of good tolerability, a rapid titration scheme in general may be used in men. Since the response on weight reduction in men seems to be delayed in comparison to women, we also advise to delay efficacy assessment in men.
The approval of once daily liraglutide, 3.0 mg, and once weekly semaglutide, 2.4 mg, for chronic weight management provides a novel effective strategy against obesity. The reliable models that might ...predict weight reducing potential at the individual level have not been identified yet. However, the coexistence of diabetes has been consistently related with less effective response than in people without this comorbidity. We aimed to review the efficacy of GLP-1 RAs approved for weight management in individuals with and without diabetes and discuss some potential mechanisms for consistently observed differences in efficacy between these two populations. The mean weight loss difference between GLP-1 RAs and placebo as add-on to lifestyle intervention in patients with diabetes was 4% to 6.2% compared to 6.1 to 17.4% in people without diabetes. Semaglutide compared to liraglutide resulted in greater weight loss. Some hypothetical explanations for the weaker anti-obesity response for both GLP-1 RAs in people with diabetes include the background medications that promote weight gain, the fear of hypoglycaemia inherently related to the treatment of diabetes, a decrease in glycosuria and subsequently less weight loss in diabetics, an altered microbiota in patients with obesity and diabetes and a genetic background that predispose to weight gain in patients with diabetes. Moreover, people with diabetes may have had obesity for longer and may be less adherent to exercise, which seems to potentiate the effects of GLP-1 RA. Emerging multimodal approaches combining peptides targeting receptors at different levels might therefore be of additional benefit particularly in patients with diabetes.
Deteriorated arterial function and high incidence of cardiovascular events characterise diabetes mellitus. Metformin and recent antidiabetic drugs, SGLT2 inhibitors, reduce cardiovascular events. We ...explored the possible effects of empagliflozin's effect on top of metformin treatment on endothelial function and arterial stiffness parameters in type 1 diabetes mellitus (T1DM) patients.
Forty T1DM patients were randomised into three treatment groups: (1) empagliflozin (25 mg daily), (2) metformin (2000 mg daily) and (3) empagliflozin/metformin (25 mg daily and 2000 mg daily, respectively). The fourth group received placebo. Arterial function was assessed at inclusion and after 12 weeks treatment by: endothelial function brachial artery flow-mediated dilation (FMD), reactive hyperaemia index (RHI), arterial stiffness pulse wave velocity (PWV) and common carotid artery stiffness (β-stiffness). For statistical analysis one-way analysis of variance with Bonferroni post-test was used.
Empagliflozin on top of metformin treatment significantly improved endothelial function as did metformin after 12 weeks of treatment: FMD 2.6-fold (P < 0.001) vs. 1.8-fold (P < 0.05) and RHI 1.4-fold (P < 0.01) vs. 1.3-fold (P < 0.05). Empagliflozin on top of metformin treatment was superior to metformin in improving arterial stiffness parameters; it significantly improved PWV and β-stiffness compared to metformin by 15.8% (P < 0.01) and by 36.6% (P < 0.05), respectively. Metformin alone did not influence arterial stiffness.
Empagliflozin on top of metformin treatment significantly improved arterial stiffness compared to metformin in T1DM patients. Endothelial function was similarly improved in all treatment groups. Empagliflozin seems to possess a specific capacity to decrease arterial stiffness, which could support its cardioprotective effects observed in large clinical studies. Trial registration Clinical trial registration: NCT03639545.
Introduction
The obesity epidemic is closely linked to the rising prevalence of type 2 diabetes (T2D). Body weight reduction remains an important challenge in patients with T2D, as it requires ...changing their overall metabolic control. Of all glucose-lowering therapies, only sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) consistently result in weight improvement. Moreover, the same two classes have important cardiovascular and renal benefits. We summarize the key available information related to the weight loss effect of SGLT2is in T2D, focusing on the unexploited potential of these drugs.
Methods
Data on weight change with SGLT2is in patients with T2D were extracted from published cardiovascular outcomes trials (CVOTs). A discussion on patient perspectives about weight change is based on key preclinical and clinical trials, meta-analyses, and reviews and is supplemented by the authors’ clinical judgment and research experience in the field.
Results
SGLT2is have a unique mode of action resulting in caloric loss through glycosuria. The anticipated weight loss with SGLT2is is not reflected in clinical trial results. There is a discrepancy between the magnitude of improvement in glycemic control and the weight loss, cardiovascular, and renal benefits obtained in large clinical trials.
Conclusion
The relationships between the magnitude of weight loss, improvement in glycemic control, and cardiorenal benefits with SGLT2i are still unclear. Potential mechanisms other than simple glycemic efficacy should be revealed and explained. Better weight control may be achieved if adequately intensive lifestyle changes are implemented and monitored in the T2D population treated with SGLT2is.
Objective
To explore the effects of oral semaglutide on glycaemic parameters, body weight, and satisfaction in the first recipient patients with type 2 diabetes mellitus in Slovenia, in a real-world ...clinical practice setting.
Methods
The first consecutive adult patients with type 2 diabetes who were eligible for oral semaglutide treatment were included in this prospective, open-label interventional study. Patients received increasing doses of oral semaglutide and were evaluated at inclusion, at 1 month, then 3–5 months after starting treatment. Fasting blood glucose, glycosylated haemoglobin (HbA1c), body weight, patient satisfaction with oral semaglutide treatment (using the validated Treatment Satisfaction Questionnaire for Medication), and adverse effects, were analysed. Statistical analyses were performed using one-way analysis of variance, and, when significant interactions were found, Bonferroni post-hoc test. A P-value <0.05 was considered statistically significant.
Results
Twenty patients (11 male: 9 female; mean age, 59.9 ± 1.5 years; mean diabetes duration, 8.5 ± 1.4 years) were included. Oral semaglutide (7 and 14 mg) significantly decreased HbA1c (from 9.4 ± 0.3% to 8.2 ± 0.2% and 7.8 ± 0.2%, respectively) and fasting plasma glucose (from 11.2 ± 0.5 mmol/L to 9.2 ± 0.7 mmol/L and 8.9 ± 0.4 mmol/L, respectively). Oral semaglutide (14 mg) significantly decreased body weight (from 100.9 ± 2.7 kg to 92.7 ± 2.4 kg). Patients reported that treatment was easy to use and expressed high global satisfaction. Mild and transient, mostly gastrointestinal, adverse effects were reported in 10 patients.
Conclusions
Oral semaglutide, the first oral glucagon-like peptide 1 receptor agonist, was effective and safe, and associated with high patient satisfaction, in its first recipients in Slovenia. The results are important for daily clinical practice involving patients with type 2 diabetes, however, due to the small study population, lack of placebo control, and short exposure to oral semaglutide, the effectiveness of oral semaglutide in clinical practice requires further investigation.
The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D ...who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.
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