Diabetes Therapy最新文献

Introduction: The expanding range of therapeutic options for type 2 diabetes (T2D) calls for a reassessment of clinical scenarios in which existing glucose-lowering therapies might be substituted with the oral glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide (OS). In light of the numerous unresolved questions, a panel of experts was convened to develop practical guidance for clinicians using the Delphi consensus method.

Methods: A panel of 13 experts formulated 31 statements addressing the following clinical scenarios: switch from injectable GLP-1 RA to OS; switch from sodium-glucose cotransporter 2 inhibitor to OS; switch from insulin to OS; switch from dipeptidyl peptidase 4 inhibitor (DPP4i) to OS; switch from "old" oral therapies (i.e., sulfonylureas, glinides, pioglitazone, acarbose) to OS. A panel of 28 diabetologists from the Emilia-Romagna region evaluated each statement by assigning a relevance score on a 9-point scale via a dedicated online platform. The RAND/UCLA Appropriateness Method was employed to determine the presence of disagreement among panelists.

Results: Panelists showed agreement for all 31 statements, all considered relevant. Panelists agreed that in many circumstances OS can represent a valuable alternative to injectable GLP-1 RAs, other oral glucose-lowering drugs, and insulin. The selection of OS is justified by its proven effectiveness in reducing glycated hemoglobin and body weight, as well as its positive impact on cardiovascular outcomes and all-cause mortality. Furthermore, OS can allow a simplification of therapy in patients treated with insulin.

Conclusion: In an ever-evolving therapeutic landscape, OS therapy stands as a valuable option in the management of patients with T2D.

Introduction: Patients with type 2 diabetes mellitus (T2DM) who cannot achieve normal glycosylated hemoglobin (HbA1c) levels are sometimes given the combined therapeutic regimen of polyethylene glycol loxenatide (PEG-Loxe) + basal insulin. The aim of this study was to investigate the efficacy and safety of PEG-Loxe combined with basal insulin in patients with T2DM.

Methods: This retrospective, real-world study included patients with T2DM aged ≥ 18 years for whom basal insulin therapy was ineffective, whose HbA1c levels were between 7.0% and 11.0%, and who were on either continued basal insulin dose adjustment or who had received PEG-Loxe + basal insulin combined therapy for at least 24 weeks. The primary endpoint was change in HbA1c level after 24 weeks treatment. Secondary endpoints included HbA1c achievement target rate, change in fasting plasma glucose and body weight, respectively, and change in HbA1c stratified by sex, age, disease duration, and baseline HbA1c level.

Results: Overall, 307 patients were identified. After propensity score matching, 44 patients each were included in the basal insulin and PEG-Loxe + basal insulin group. After 24 weeks, a significant difference in Hb1Ac reduction between the groups (P = 0.003) was observed. Also, patients treated with PEG-Loxe + basal insulin combined therapy experienced greater body weight reduction compared those treated with basal insulin only (intergroup difference: - 3.2 kg; 95% confidence interval [95% CI] - 5.4, - 1.0]; P = 0.005). There was a significant intergroup difference in weight reduction in patients with body mass index ≥ 28 kg/m² (- 8.4 kg; 95% CI - 13.9, - 3.0; P = 0.004). HbA1c levels in female patients aged < 65 years with HbA1c ≥ 8.5% and with a disease duration ≥ 10 years were significantly different between the two treatment groups (P < 0.005). Hypoglycemic events occurred in 10.4% of patients treated with PEG-Loxe + basal insulin with no cases of level 3 hypoglycemia.

Conclusion: PEG-Loxe + basal insulin combined therapy was safe and effective in patients with T2DM who did not achieve optimal glycemic control with insulin therapy alone.

Trial registration: ClinicalTrials.gov identifier: ChiCTR2400086699.

Introduction: People with chronic kidney disease (CKD) and type 2 diabetes (T2D) have an increased risk of kidney failure and cardiovascular disease. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have shown cardiorenal protective effects. The objective of this multinational, multidatabase study was to describe the incidence of kidney and cardiovascular outcomes in separate, non-mutually exclusive cohorts of patients with CKD and T2D who initiated either an SGLT2i or a GLP-1 RA.

Methods: Data describing adults (≥ 18 years) with T2D and CKD who were new users of either SGLT2i or GLP-1 RA from 2012 to 2019 were assessed from population-based Danish National Health Registers (DNHR) and Valencia Health System Integrated Database (VID), hospital-based Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex), and US Optum^® de-identified Electronic Health Record dataset (Optum^® EHR). Crude incidence rates (IRs) and 95% confidence intervals (CIs) for primary outcomes (kidney failure, acute coronary syndrome, stroke, new-onset congestive heart failure, new-onset atrial fibrillation) and cumulative incidence by follow-up time for primary and secondary outcomes (laboratory measurements of kidney function) were estimated.

Results: SGLT2i cohorts comprised 12,501 patients in DNHR, 22,404 in VID, 811 in J-CKD-DB-Ex, and 54,308 in Optum^® EHR. GLP-1 RA cohorts comprised 10,696 in DNHR, 8317 in VID, 219 in J-CKD-DB-Ex, and 78,934 in Optum^® EHR. Baseline clinical profile differences were observed for GLP-1 RA and SGLT2i new users, and crude IRs of kidney and heart failure tended to be higher in the GLP-1 RA cohorts than in the SGLT2i cohorts across data sources.

Conclusion: Understanding the incidence of kidney failure and cardiovascular outcomes in people receiving antidiabetic medications with cardiorenal protective effects is important for future studies aiming to compare the incidence of kidney and cardiovascular outcomes related to new and existing CKD treatments.

Introduction: Obesity prevalence has increased in Finland and is prevalent in patients with type 2 diabetes (T2D). Also, hyperglycemia in patients with T2D is partially attributed to obesity. We aimed to examine the time trends of body mass index (BMI) and glycated hemoglobin (HbA1c) control across different BMI categories among Finnish patients with T2D.

Methods: Regional data on the electronic health records (EHRs) covering all public healthcare services in North Karelia, Finland, were used to conduct this retrospective study. Annual patients with T2D from 2012 to 2022 were identified from the EHRs. In each study year, patients with ≥ 1 measurement of BMI and HbA1c were included. Linear and logistic regression analyses estimated with generalized estimating equations were performed to evaluate the time trends.

Results: The annual number of patients for analyses ranged from 5149 to 10,216 during 2012-2022. The unadjusted mean BMI declined slightly over time but increased after age adjustment (all p < 0.05). In the age-stratified analysis adjusted for sex and diabetes duration, mean BMI increased over time in patients aged 45-64 years (all p < 0.05). Furthermore, the increasing time trend in age-adjusted BMI among the study patients persisted after adjusting for sex, diabetes duration, and antidiabetic medication use (p < 0.05). Overall, patients in the higher BMI categories had higher HbA1c levels and were less likely to achieve the HbA1c target from 2012 to 2022. When examining time trends of HbA1c control, HbA1c control improved over time in patients with the highest level of BMI, coinciding with a greater increase in new antidiabetic medication use compared with the lowest BMI group (p < 0.05 for calendar year × obesity class III interaction).

Conclusion: Our findings suggest that weight management requires increased attention among Finnish patients with T2D and is especially important for better glycemic control.

Introduction: The ONWARDS programme assessed the efficacy and safety of once-weekly insulin icodec (icodec) versus once-daily basal insulin comparators in type 2 diabetes (T2D) or type 1 diabetes (T1D). This post hoc exploratory analysis of ONWARDS 1-6 assessed the impact of icodec during and around hospitalisation.

Methods: ONWARDS 1-6 were randomised, two-arm, phase 3a trials (ClinicalTrials.gov: NCT04460885; NCT04770532; NCT04795531; NCT04880850; NCT04760626; NCT04848480). Adults with T2D (ONWARDS 1-5; n = 3765) and T1D (ONWARDS 6; n = 582) received icodec or once-daily comparators (insulin degludec, insulin glargine U100, insulin glargine U300). Hospitalised cases were analysed for: hospitalisation duration, icodec dose, self-measured blood glucose, glycated haemoglobin (HbA_1c) levels, and clinically significant and severe hypoglycaemia before, during, and after hospitalisation.

Results: Across trials, a similar number of participants receiving icodec (n = 152/2172) and once-daily comparators (n = 156/2175) were hospitalised. Median duration of hospital stay was similar between treatment groups (icodec, 5.0 days; once-daily comparators, 6.0 days); icodec dose remained fairly stable around hospitalisation. Most hospitalised participants completed the trial without permanently discontinuing treatment (icodec, 84.9%; once-daily comparators, 90.4%). Mean HbA_1c levels remained relatively stable over assessed time points for both treatment groups. Six participants receiving icodec (one with T2D; five with T1D) and three receiving once-daily comparators (one with T2D; two with T1D) reported clinically significant or severe hypoglycaemia during hospitalisation.

Conclusions: Similar numbers of hospitalisations were reported in both treatment arms. Icodec treatment was continued during hospitalisation in most participants and did not appear to have an impact on glycaemic management or hypoglycaemia. This analysis suggests that once-weekly icodec could be managed in a similar way to once-daily basal insulin analogues during hospitalisation.

Trial registration: ClinicalTrials.gov identifiers, NCT04460885 (ONWARDS 1), NCT04770532 (ONWARDS 2), NCT04795531 (ONWARDS 3), NCT04880850 (ONWARDS 4), NCT04760626 (ONWARDS 5), NCT04848480 (ONWARDS 6).

Introduction: A post hoc analysis from a 90-day proof-of-concept study demonstrated increased efficacy and no new safety concerns for an ultra-rapid-acting inhaled insulin, Technosphere^® Insulin (TI), when a higher modified conversion dose was compared to the conversion dose in the current US prescribing insert (approx. 2 × vs approx. 1.3 × TI per rapid-acting insulin analogue [RAA] unit [U] across the 1-24 U range). This post hoc analysis evaluates the safety and efficacy of the modified conversion dose in the postprandial period.

Methods: Participants with type 1 diabetes (T1D) were randomly assigned to administer TI using the modified dosing (TI group) or continue using their automated insulin delivery (AID) system (AID controls) in this in-clinic standardized meal challenge. Postprandial glucose was measured via capillary self-monitored blood glucose over 2 h post-meal to evaluate mean peak glucose and mean peak glucose excursion.

Results: The TI group (n = 21) demonstrated faster and lower mean peak glucose and mean peak glucose excursion vs AID controls (n = 5). Mean peak glucose and glucose excursion were reached 30 min earlier with TI. One TI + AID participant (modified dose) experienced one level 1 hypoglycemia event in the 2-h postprandial period and recovered in-clinic. No serious adverse events were reported.

Conclusions: TI group demonstrated a more favorable glycemic response in the 2-h postprandial period vs AID control. Data from this and previous studies suggest this higher modified conversion TI dose from subcutaneous RAA may help further reduce postprandial hyperglycemia in T1D.

Trial registration: ClinicalTrials.gov NCT05243628.

Introduction: The rising prevalence of diabetes has driven extensive research into effective management strategies, emphasizing the importance of integrating self-management routines into daily life. This study presents real-world observations on the impact of the mySugr^® app, used in conjunction with the Accu-Chek^® Instant blood glucose monitoring device, on glycemic control and patient satisfaction in India.

Methods: This retrospective, observational, non-interventional study was conducted at 29 sites in India, involving people with diabetes (PwD) who used the mySugr^® app in conjunction with the Accu-Chek^® Instant glucose meter for at least 3 months. Data from electronic health records and paper-based records were analyzed. The primary objective was to evaluate changes in glycated hemoglobin (HbA1c) levels over 3 months. Additionally, the study assessed the frequency of hypoglycemic and hyperglycemic events, changes in HbA1c based on monitoring frequency, and the use of insulin and non-insulin therapies. Patient satisfaction with the mySugr^® app was also assessed.

Results: A total of 111 PwD were included and had an average age of 53.2 years. The mean HbA1c level significantly decreased from 8.8% to 7.5% (p < 0.0001) in PwD using the mySugr^® app in conjunction with the Accu-Chek^® Instant glucose meter for at least 3 months. Frequent monitoring (≥ 6 times per week) resulted in a greater HbA1c reduction (1.5%-points) compared to less frequent monitoring (1.0%-point). Insulin-treated PwD showed a larger HbA1c reduction (1.6%-points) compared to those not on insulin (0.8%-points). PwD reported an average of 1.9 hypoglycemic and 20.0 hyperglycemic events.

Conclusion: The mySugr^® app, used in conjunction with the Accu-Chek^® Instant glucose meter, demonstrated improved glycemic control. Future research should focus on larger, diverse samples and long-term evaluations to confirm these findings and explore the cost-effectiveness of integrating such applications into routine diabetes care.

Introduction: This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of the ketohexokinase inhibitor LY3522348 in healthy participants.

Methods: This first-in-human phase 1 study evaluated LY3522348, a highly selective, oral dual inhibitor of human ketohexokinase (KHK) isoforms C and A. The study was conducted in two parts: a single-ascending dose (SAD) study and a multiple-ascending dose (MAD) study, including a drug-drug interaction analysis with midazolam. Participants in the SAD study received single oral doses of LY3522348 ranging from 5 to 380 mg, while participants in the MAD study received once-daily doses of 50 mg, 120 mg, and 290 mg for 14 days.

Results: A total of 65 healthy participants were included; of these 40 were in the SAD study (placebo = 10; LY3522348: 5 mg = 6; 15 mg = 6; 50 mg = 6; 150 mg = 6; 380 mg = 6) and 25 in the MAD study (placebo = 6; LY3522348: 50 mg = 6; 120 mg = 6; 290 mg = 7). LY3522348 was well tolerated, with the majority of the reported adverse events being mild. PK analysis showed an approximately dose-proportional increase in LY3522348 exposure, and the half-life ranged from 23.7 to 33.8 h. PD analysis indicated a dose-dependent increase in plasma fructose concentrations following the administration of a fructose beverage, supporting the inhibition of fructose metabolism by LY3522348.

Conclusions: LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism. The study was registered on ClinicalTrials.gov (NCT04559568).