OBJECTIVE: Diabetic nephropathy represents the leading cause of end-stage kidney disease in developed countries. Cardiovascular outcome trials have found that in participants who received a glucagon-like peptide-1 receptor agonist (GLP1RA) and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), the risk of incidence and progression of diabetic nephropathy in type 2 diabetes mellitus was reduced. The aim of this study was to compare the decline in estimated glomerular filtration rate (eGFR) among people taking a GLP1RA with that among people taking an SGLT2i in a real-world setting.
METHODS: Data for 478 patients with type 2 diabetes mellitus who initiated therapy with a GLP1RA (n = 254) or an SGLT2i (n = 224) between January 1, 2018 and December 31, 2021 were extracted. The primary outcome was any reduction ≥30% in eGFR after the start of therapy. Weight loss and drug discontinuation were also assessed.
RESULTS: Over a median follow-up of 24 months, an eGFR reduction ≥30% occurred in 34 of 254 patients (13.4%) starting a GLP1RA and in 26 of 223 patients (11.6%) starting an SGLT2i (hazard ratio = 0.89; 95% CI, 0.54-1.49; P = 0.67). Median eGFR change over the whole follow-up was similar between groups (SGLT2i: median, -2 mL/min/1.73 m2; 25th, 75th percentile, -13, 8 mL/min/1.73 m2; GLP1RA: median, 0 mL/min/1.73 m2; 25th, 75th percentile, -10, 7 mL/min/1.73 m2; P = 0.54). No worsening of kidney function was observed, even when considering the ratio eGFR mean. The value of eGFR at baseline indicated a statistically significant indirect correlation with the observed absolute value of eGFR change over the follow-up (ρ = -0.36; P < 0.001). The difference in eGFR changes over time observed by eGFR categories was statistically significant (P = 0.0001) in both treatment groups. No significant differences in weight loss and drug discontinuations were observed between groups.
CONCLUSIONS: Although acting on different molecular mechanisms, both GLP1RA and SGLT2i might have similar effects on eGFR decline in diabetes, as suggested by the results of the present study conducted in a real-world setting. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Oral semaglutide has potent anti-hyperglycemic efficacy in phase III trials. However, the complicated dosing instructions hamper to use this drug; therefore, we evaluated the efficacy and safety of oral semaglutide in subjects with type 2 diabetes in a real-world clinical setting. In this multi-center retrospective observational study, we analyzed subjects with type 2 diabetes newly treated with an oral semaglutide for >6 months at four medical centers located in Sapporo, Japan. The changes in glycated hemoglobin, body weight, and other metabolic parameters were evaluated and any adverse event leading to semaglutide discontinuation were recorded from February 2021 to December 2022. This study was registered with the University Hospital Medical Information Network Center (UMIN000050583). Of 543 subjects who met the inclusion criteria, data for 434 subjects (age 55.5 ± 12.6 years; body mass index 29.6 ± 6.0 kg/m2) were analyzed. After a 6 months of observation period, semaglutide 3 mg, 7 mg, or 14 mg was used by 55 (12.7%), 241 (55.5%), and 138 (31.8%) of subjects, respectively. Both glycated hemoglobin and body weight significantly improved: 7.65 ± 1.11% to 6.88 ± 0.91% (p < 0.001) and 80.2 ± 19.2 kg to 77.6 ± 19.2 kg (p < 0.001), respectively. Efficacy was also confirmed in the subgroup switched from other anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors. In total, 154 subjects had symptomatic gastrointestinal symptoms and 39 (7.2%) were discontinued semaglutide due to the adverse events. None of the participants experienced severe hypoglycemic events. Oral semaglutide in subjects with type 2 diabetes improved glycemic control and body weight in a real-world clinical setting.

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM.

To present the final results of the TROPHIES study (The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in patients with type 2 diabetes).
The prospective, real-world TROPHIES study included patients with type 2 diabetes initiating their first injectable glucose-lowering medication (GLM), dulaglutide or liraglutide, in France, Germany and Italy. The primary endpoint was the time spent on dulaglutide or liraglutide until a significant treatment change over 24 months. Other endpoints measured persistence with treatment, clinical outcomes (glycated haemoglobin [HbA1c] and weight) and treatment patterns. Kaplan-Meier estimates of time to first significant treatment change and persistence with treatment were generated. Propensity-score-based inverse probability of treatment weighting (IPTW) was used to adjust for baseline imbalances in the comparison between cohorts.
The 286 of 1014 patients (28.2%) in the dulaglutide cohort and 448 of 991 patients (45.2%) in the liraglutide cohort had a significant treatment change over 24 months. By IPTW analysis, dulaglutide-initiating patients were less likely to have a significant treatment change (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.46-0.63) and more likely to be persistent with treatment (HR 0.69, 95% CI 0.56-0.86) over 24 months than liraglutide-initiating patients. Dulaglutide and liraglutide yielded similar HbA1c (-11.80 mmol/mol [1.08%] and -11.91 mmol/mol [1.09%]) and weight (-3.5 kg and -3.3 kg) reductions from baseline to 24 months. Few changes in patterns of treatment with other GLMs were observed in the two cohorts.
Dulaglutide-initiating patients had a longer time spent without any significant treatment change and higher persistence than those initiating liraglutide. Treatment with either glucagon-like peptide-1 receptor agonist yielded similar and clinically meaningful reductions in HbA1c and body weight.

OBJECTIVE: To compare the effectiveness and safety of empagliflozin and dulaglutide in patients with type 2 diabetes (T2D) inadequately controlled by oral triple therapy.
METHODS: In this 24-week, multi-center, randomized trial, patients with T2D and HbA1c level ≥7.5% (58 mmol/mol) on metformin, sulfonylurea, and dipeptidyl peptidase 4 inhibitor (DPP4-i) were randomly assigned into two groups: daily empagliflozin add-on or once-weekly dulaglutide switched from DPP4-i. The primary endpoint was changes from baseline HbA1c at 24 weeks.
RESULTS: In total, 152 patients were recruited to the empagliflozin-added quadruple group (n = 76) or the switched-to-dulaglutide triple group (n = 76). At week 24, both groups showed significant reduction in HbA1c level from baseline with greater reduction with empagliflozin (the mean treatment difference: -0.27% [95% CI -0.50 to -0.04, p = 0.024]) (-2.88 mmol/mol [95% CI -5.37 to -0.39], p = 0.024). Empagliflozin significantly reduced body weight from baseline to week 24 (-1.72 kg [95% CI -1.98 to -0.59, p < 0.001]). No serious adverse events were reported with either empagliflozin or dulaglutide.
CONCLUSIONS: Empagliflozin, compared with once-weekly dulaglutide switched from DPP4-i, demonstrated greater HbA1c reduction and weight loss in patients with T2D inadequately controlled with metformin, sulfonylurea, and DPP4-i.
BACKGROUND: cris.nih.go.kr (KCT0006157).

Glucagon-like peptide-1 receptor agonist liraglutide may have beneficial effects on atherosclerosis development in impaired glucose tolerance (IGT). To the best of our knowledge, however, little conclusive evidence from clinical trials has been presented. The present study aimed to investigate the effect of liraglutide on atherosclerosis progression in patients with IGT. The present study was a double-blind, randomized controlled clinical trial. A total of 39 of patients aged 20-75 years who were overweight or obese (BMI, 27-40 kg/m2) and presented IGT were randomized to receive liraglutide (n=17) or lifestyle interventions (n=22) for 6 months. Serum glucose and insulin (INS) levels, lipid profile, inflammatory biomarkers and carotid intima-media thickness (CIMT) were assessed at the start and end of each treatment. Side effects were also recorded. Liraglutide treatment was found to significantly improve glycaemia, including glycosylated hemoglobin, fasting and postprandial glucose as well as INS levels (all P<0.001). Liraglutide also significantly decreased serum total cholesterol and low-density lipoprotein levels (all P<0.001). Furthermore, serum levels of inflammatory biomarkers, as well as CIMT, were decreased following liraglutide treatment compared with those in the lifestyle intervention group (all P<0.001). Kaplan-Meier analysis showed that the risk of vasculopathy in the liraglutide group was lower than that in the lifestyle intervention group (log-rank test; P=0.041). The monitoring of drug-associated side effects indicated that the dose of liraglutide (0.6 to 1.2 mg/QD via subcutaneous injection) was safe and well-tolerated. The present study suggested that liraglutide may slow atherosclerosis development and improve inflammatory status as well as intimal function in patients with IGT with few side effects. The trial was registered through the Chinese Clinical Trial Registry (ChiCTR; trial registration no. ChiCTR2200063693; retrospectively registered) on Sep 14, 2022.

Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion.
The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32.
Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation.
Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation.
Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.
FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.
Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.
FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Clinical studies after marketing have shown that the use of glucagon-like peptide-1 receptor agonist(GLP-1RA) may lead to acute kidney injury(AKI). However, few epidemiological studies have investigated the risk, clinical features, and outcomes of AKI caused by different GLP-1RA. In this study, Adverse Event Reporting System (FAERS) data were used to compare the association between different GLP-1RA and AKI in the real world.
FAERS data from January 2004 to December 2021 were mined using disproportionality analysis and Bayesian analysis to determine the correlation between different GLP-1RA and AKI, and the onset time, mortality, and hospitalization rate of different GLP-1RA were analyzed.
We identified 2670 cases of AKI events associated with GLP-1RA, of which liraglutide was the most commonly reported (34.98%). The patients with AKI were mainly males (47.94%), and the age group was mainly 45-84 years old (73.15%). obese patients with weight more than 99kg (24.42%) were more likely to have AKI. According to different signal mining methods, reporting odds ratio (ROR) (1.50, 95% confidence interval =1.41-1.60) and Bayesian confidence Propagation neural network (0.57, 95% confidence interval =0.54), liraglutide was more strongly associated with AKI than other GLP-1RA. The median time to onset of AKI was 63 days [quartile range (IQR): 15-458.5 days]. In addition, the hospitalization rate and fatality rate of patients with GLP-1RA-related AKI were 45.28% and 4.23% respectively.
Based on the data in the FAERS database, we analyzed the risk, onset time, and adverse reaction outcomes of GLP-1RA-induced AKI in detail. The results showed that liraglutide had the highest risk of AKI. From the early stage of treatment, we need to monitor patients\' renal function regularly, especially for patients with high kidney risks such as obesity and age.

This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM).
This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight.
In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to -67.89 (-88.98, -46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [up to -1.41% (-2.01%, -0.82%)] and body weight [up to -1.87 (-3.58, -0.17) kg].
In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action.