Patient-important outcomes in type 2 diabetes: The paradigm of the sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists.

The newfound knowledge in type 2 diabetes (T2D) during the past decade for the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is wealthy in favorable results for key patient-important outcomes including morbidity, mortality and health-related quality of life (HRQoL). The SGLT-2i and GLP-1RA offer cardiovascular and renal protection beyond their glucose lowering effect, reduce body weight and hypoglycemia and improve diabetes-related distress, physical function and HRQoL. Along with the fixed-ratio combinations of basal insulin/GLP-1RA, they make feasible a regimen simplification and de-escalation from high dose and multiple injections of insulin reducing treatment burden. Besides cardiorenal risk reduction, the SGLT-2i and GLP-1RA reduce the incidence of depression, cognitive decline, respiratory disease, gout, arrhythmias and other co-occurring conditions of T2D, namely multimorbidity, which frequently complicates T2D and adversely affects HRQoL. The alleviation of multimorbidity by the pleiotropic effects of the SGLT-2i and GLP-1RA, could improve patients' HRQoL. The use of the SGLT-2i and GLP-1RA should be increased within a shared decision-making in which they are reframed as cardiorenal risk-reducing medications with the potential to lower blood glucose. By improving outcomes that patients may highly perceive and value, the SGLT-2i and GLP-1RA may facilitate the contemporary person-centered management of T2D.

Effect of fixed-ratio insulin combinations on adherence in type 2 diabetes: Systematic review.

AIMS: To systematically review evidence on the effect of fixed-ratio combinations on adherence in people with type 2 diabetes. METHODS: Systematic searches were conducted using MEDLINE and EMBASE in March 2023. Standardised screening, data extraction and risk of bias assessment were conducted. All review procedures were conducted independently by two reviewers. Eligible studies assessed the effect of fixed-ratio combinations on adherence in people with type 2 diabetes. Narrative synthesis was conducted to analyse findings. RESULTS: A total of 488 records were identified, of which 37 proceeded to full-text screening and 7 - each representing a unique study - were included in the systematic review. Among the included studies, 3 were randomised controlled trials and 4 were cohort studies. Following narrative synthesis, it was shown that fixed-ratio combinations improved patient satisfaction and treatment adherence. CONCLUSIONS: Available evidence supports a benefit for fixed-ratio combinations on patient satisfaction and treatment adherence in people with type 2 diabetes.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). RESULTS: Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD) = 0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD = -2.06 kg; 95% CI: -3.34 to -0.77), SBP (MD = -1.22 mmHg; 95% CI: -2.41 to -0.04), and DBP (MD = -1.09 mmHg; 95% CI: -1.94 to -0.24) between the two groups. CONCLUSIONS: In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.

Expert Opinion on Optimising Type 2 Diabetes Treatment Using Fixed-Ratio Combination of Basal Insulin and GLP-1 RA for Treatment Intensification and Simplification.

The management of type 2 diabetes (T2D) often necessitates treatment intensification, and sometimes simplification to achieve glycaemic targets and mitigate complications. This expert opinion paper evaluates the use and positioning of the fixed-ratio combinations (FRCs) of basal insulin (BI) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in optimising T2D management. On the basis of the evidence presented and discussions, these FRCs offer a promising approach for both treatment intensification and simplification in people with suboptimal glucose control despite receiving various therapies. In treatment intensification, FRCs provide a synergistic effect by addressing multiple pathophysiological defects contributing to hyperglycaemia. These FRCs effectively control both fasting and postprandial glucose (PPG) excursions, offering significantly improved glycaemic control with a lower hypoglycaemia risk and weight neutrality compared to traditional or complex insulin regimens. Moreover, the reduced injection frequency (once daily) and flexibility in the dosing schedule (with any major meal of the day) help mitigate patient resistance to insulin initiation or titration. This further reduces treatment burden, facilitating treatment adherence and enhancing patient convenience. These key benefits of FRCs over complex insulin regimens play a crucial role in long-term glycaemic management and overall treatment outcomes. Hence, the timely use of FRCs in the treatment algorithm for people with T2D represents a valuable strategy for optimising glycaemic control, addressing treatment barriers and enhancing patient-reported outcomes.

Treatment intensification following glucagon-like peptide-1 receptor agonists in type 2 diabetes: Comparative effectiveness analyses between different basal insulins. RESTORE-G real-world study.

AIM: To compare the effectiveness of different basal insulins (BI) prescribed as an add-on to or switch from glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy. MATERIALS AND METHODS: Retrospective, real-world data from electronic medical records of 32 Italian diabetes clinics were used, after propensity score adjustment, to compare effectiveness after 6 months of treatment with second- versus first-generation BI (2BI vs. 1BI) or glargine 300 U/ml versus degludec 100 U/ml (Gla-300 vs. Deg-100), when added to (ADD-ON) or in substitution of (SWITCH) GLP-1 RA. Only comparisons, including a minimum of 100 patients per group, were performed to ensure adequate robustness of the analyses. RESULTS: In the ADD-ON cohort (N = 700), greater benefits of 2BI versus 1BI were found in glycated haemoglobin {HbA1c; estimated mean difference: -0.32% [95% confidence interval (CI) -0.62; -0.02]; p = .04} and fasting blood glucose [FBG; -20.73 mg/dl (95% CI -35.62; -5.84); p = .007]. In the SWITCH cohort (N = 2097), greater benefits of 2BI versus 1BI were found in HbA1c [-0.22% (95% CI -0.42; -0.02); p = .03], FBG [-10.15 mg/dl (95% CI -19.04; -1.26); p = .03], and body weight [-0.67 kg (95% CI -1.30; -0.04); p = .04]. In the SWITCH cohort starting 2BI (N = 688), marked differences in favour of Gla-300 versus Deg-100 were documented in HbA1c [-0.89% (95% CI -1.26; -0.52); p < .001] and FBG [-17.89 mg/dl (95% CI -32.45; -3.33); p = .02]. Using propensity score matching as a sensitivity analysis, the benefit on HbA1c was confirmed [-0.55% (95% CI -1.02; -0.08); p = .02]. BI titration was suboptimal in all examined cohorts. CONCLUSIONS: 2BI are a valuable option to intensify GLP-1 RA therapy. Switching to Gla-300 versus Deg-100 was associated with greater HbA1c improvement.

The efficacy and safety of iGlarLixi versus IDegAsp in Chinese people with type 2 diabetes suboptimally controlled with oral antidiabetic drugs: The Soli-D randomized controlled trial.

AIM: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). METHODS: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. RESULTS: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. CONCLUSIONS: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study.

BACKGROUND AND AIMS: Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. METHODS AND RESULTS: Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: -24.05 mg/dl (-37.04; -11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. CONCLUSION: Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

The IDEAL (Insulin therapy DE-intensificAtion with iglarLixi) Randomised Controlled Trial-Study Design and Protocol.

INTRODUCTION: Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently a substantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100 U/ml and a GLP-1 RA lixisenatide. METHODS: Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. PLANNED OUTCOMES: The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04945070.

Real-world effectiveness and safety of insulin glargine 100 U/mL plus lixisenatide in adults with type 2 diabetes: An international, multicentre, 12-month, prospective observational study.

AIM: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). MATERIALS AND METHODS: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6. RESULTS: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year]). CONCLUSIONS: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia.

Impact of Participant Characteristics on Clinical Outcomes with iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of SPARTA Japan.

INTRODUCTION: The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) once daily over 6 months in Japanese people with type 2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. METHODS: The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6 months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. RESULTS: In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. CONCLUSIONS: Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6 months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

iGlarLixi is an injectable product used to treat type 2 diabetes that contains a fixed combination of two drugs, insulin glargine (at a concentration of 100 U/mL) and lixisenatide. The SPARTA Japan study investigated the effectiveness of controlling blood glucose levels and the safety of iGlarLixi in Japanese people when taken once daily for over 6 months as part of their routine medical care. The analysis reported in this article looked back at data from SPARTA Japan to assess whether certain characteristics of the people who took part in the study affected how well blood glucose targets were met. People who had previously taken insulin and those who had not were identified, and their results were assessed separately. The people were divided into those who had met their blood glucose level target (with the target defined as the glycated haemoglobin level for each person based on their age) and those who had not met their target. It was found that people who achieved their blood glucose target while receiving iGlarLixi were more likely to be older, to have had a lower glycated haemoglobin level before starting iGlarLixi, and to have lost weight during treatment than those who did not achieve their target, whether or not they had previously been treated with insulin. Side effects of excessively low blood glucose levels or gastrointestinal upset with iGlarLixi treatment occurred in a similar number of people who achieved or did not achieve their blood glucose target.

BEYOND 2 years: durability of metabolic benefits by simplification of complex insulin regimens in type 2 diabetes.

PURPOSE: To assess the magnitude and durability of the metabolic benefits by simplification of complex insulin treatments in patients with type 2 diabetes inadequately controlled by a full basal-bolus insulin regimen. Herein we report the results of the scheduled 2-year extension of the BEYOND trial. METHODS: Originally, 305 participants with inadequate glycemic control (HbA1c > 7.5%) were randomly assigned to intensification of basal-bolus insulin regimen (n = 101), to a fixed-ratio combination (basal insulin + GLP-1RA, n = 102), or to an association of basal insulin plus an SGLT-2 inhibitor (gliflo-combo, n = 102). The primary efficacy outcome was change from baseline in HbA1c at 24 months assessed by an intention-to-treat analysis. A per-protocol analysis was also performed. RESULTS: Fifty-five percent of patients completed the study in the two comparison arms. Compared with patients randomized to basal-bolus, patients of the other groups experienced non statistically different reductions in HbA1c level according to either an intention-to-treat analysis (-0.8 ± 1.1%, -0.7 ± 1.1%, and -1.3 ± 1.1%, mean ± SD, fixed-ratio, gliflo-combo and basal bolus, respectively) or per-protocol analysis (-1.2 ± 1.0%, -1.2 ± 1.1%, and -1.3 ± 1.0%, respectively). The final HbA1c level (per protocol) was 7.2 ± 0.8%, 7.3 ± 0.9%, and 7.5 ± 0.9%, respectively (P = NS). Treatment satisfaction (DTSQ) increased in both exchange groups, whereas the proportion of patients with hypoglycemia was lower. CONCLUSION: Simplification of complex insulin regimen may be a durable option in at least one-half of patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION: Clinical trial registration no. NCT04196231, clinicaltrials.gov.

The change in Fibrosis-4 index in Japanese patients with type 2 diabetes treated by a fixed-ratio combination therapy of insulin degludec and liraglutide: A retrospective observational study.

AIM: The efficacy of titratable fixed-ratio combination therapy by a combination preparation of insulin degludec and liraglutide (IDegLira) in Japanese patients with type 2 diabetes, focusing particularly on the change in Fibrosis-4 index (FIB-4), a noninvasive method for the evaluation of liver fibrosis, was investigated. METHODS: As the full analysis set, 113 patients were treated with IDegLira. The patients were categorized into two groups according to the absence (GLP-1RA-naïve group, n = 72) or presence (GLP-1RA-treated group, n = 41) of glucagon-like peptide-1 receptor agonist (GLP-1RA) use before starting IDegLira. The clinical parameters were retrospectively determined over 6 months. RESULTS: The glycated hemoglobin value was significantly reduced in both groups. The bodyweight significantly decreased from 67.4 ± 11.0 kg at baseline to 66.4 ± 11.6 kg at 6 months in the GLP-1RA-naïve group, although it slightly increased in the GLP-1RA-treated group. FIB-4 significantly decreased from 1.60 ± 0.84 at baseline to 1.49 ± 0.74 at 6 months in the GLP-1RA-naïve group. Although FIB-4 significantly increased in the GLP-1RA-treated group, it remained within the low-risk level for liver fibrosis. CONCLUSION: Fixed-ratio combination therapy using IDegLira for the treatment of type 2 diabetes is useful for glycemic control and weight management. In particular, IDegLira may be more effective for lowering FIB-4 than adding unused oral antidiabetic agents or increasing the dose of insulin in GLP-1RA-naïve patients.

Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis.

Background: Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA-have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice. Methods: In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ2) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878). Findings: 40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD -0.40%, 95% CI [-0.66; -0.14], low certainty; vs. iGlarLixi MD -0.48%, 95% CI [-0.75; -0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD -6.56 kg, 95% CI [-7.38; -5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD -4.61 kg, 95% CI [-5.29; -3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes. Interpretation: Aiming to support clinicians in tailoring treatment to patients' needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA. Funding: Fondazione per la Ricerca Biomedica "Saverio e Isabella Cianciola" and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8-Project Age-It: Ageing Well in an Ageing Society.

Activation of the basolateral or the central amygdala dampened the incentive motivation for food reward on high fixed-ratio schedules.

The amygdala plays crucial roles in emotional processing, motivated behaviors, and stress responses. It receives sensory information and modulates fear- and anxiety-related behaviors. Neuronal activations are induced in the basolateral complex of the amygdala (BLA) and the central nucleus of the amygdala (CeA) when exposing to acute stress, leading to increased alertness and proper behavioral adaptation. Previous studies have shown that animals displayed a decrease in appetitive motivated behaviors under stress conditions. However, whether the hyperactive amygdala is responsible for the decrease in appetitive motivated behaviors remains unknown. In this study, we aimed to examine the role of BLA or CeA activation in effort-based motivated behavior. We pharmacologically activated the BLA or the CeA with N-methyl-D-aspartate (NMDA) before the lever-pressing for food reward test on different fixed-ratio (FR) schedules (FR1, FR16, or FR32) in male Long-Evans rats. Our data showed that activation of either the BLA or the CeA with NMDA (0.05 µg in 0.5 µl per site) decreased the lever-pressing behavior on higher FR schedules of FR16 and FR32, but not on the FR1 test. Importantly, locomotor activity and free-feeding food intake were intact under amygdala activation, suggesting that the decrease in lever-pressing behavior was not due to motor disablement or decreased appetite. These results suggested that activation of the BLA or the CeA negatively impaired the effort-based motivated behavior that the animals were less willing to work for food reward.

Treatment intensification following glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes: The RESTORE-G real-world study.

BACKGROUND AND AIMS: To assess intensification approaches with basal insulin (BI) following glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment in type 2 diabetes (T2D). METHODS AND RESULTS: Real-world data were collected in electronic medical records by 32 Italian diabetes clinics between 2011 and 2021. Primary endpoint was the proportion of insulin-naïve T2D patients treated with GLP-1 RA who initiated (add-on or switch) BI. Secondary endpoints were: treatment approaches, mean time to BI start, effectiveness and safety. Among 7,962 eligible patients, BI was prescribed to 3,164 (39.7%; 95%CI 38.7; 40.8): 67.6% switched to BI (22.1% also starting 1-3 injections of short-acting insulin), 22.7% added BI while maintaining GLP-1 RA, and 9.7% switched to a fixed-ratio combination of GLP-1 RA and BI (FRC). Median time since the first GLP-1 RA to BI/FRC prescription was 27.4 (IQ range 11.8-53.5) months. In this study 60.3% of patients did not start BI/FRC, among whom 15.2% intensified GLP-1 RA therapy with other oral agents. Effectiveness and safety were documented in all intensification approaches with BI/FRC, but HbA1c level at intensification time of ≥9.0% and suboptimal BI titration suggested clinical inertia. Use of second generation BI and add-on to GLP-1 RA schemes increased over time and effectiveness improved. CONCLUSION: Clinical inertia should be overcome using innovative insulin options. Timely combination therapy of BI and GLP-1 RA is a valuable choice.

Distinct hypoglycemic effect of different formulations of a fixed ratio of basal insulin plus glucagon-like peptide-1 receptor agonist in a patient with pancreatic diabetes.

Fixed-ratio combination injection therapy (FRC) is a fixed-ratio mixture containing basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection for the treatment of patients with type 2 diabetes. The two types of FRC products contain different concentrations and mixing ratios of basal insulin and GLP-1 RA. Both products demonstrated satisfactory blood glucose control throughout the day, with less hypoglycemia and weight gain. However, few studies have examined the differences in the actions of the two formulations. Herein, we present a case of a 71-year-old man with pancreatic diabetes and significantly impaired intrinsic insulin secretion capacity, who demonstrated a marked difference in glycemic control following treatment with two different FRC formulations. Treatment with IDegLira, an FRC product, demonstrated suboptimal glucose control in the patient. However, after a change in therapy to another FRC product, IGlarLixi, his glucose control markedly improved, even with a decrease in the injection dose. This difference could have been due to lixisenatide, a short-acting GLP-1RA contained in IGlarLixi, which exerts a postprandial hypoglycemic effect irrespective of intrinsic insulin secretion capacity. In conclusion, IGlarLixi has the potential to achieve good fasting and postprandial glucose control with a once-daily injection, even in patients with type 2 diabetes who have a reduced intrinsic insulin secretion capacity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00621-5.

The Wedding Bells Sound Really Good! iGlarLixi Fixed-Ratio Combination in the Treatment of Type 2 Diabetes: A Narrative Review.

iGlarLixi is a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide used in the treatment of type 2 diabetes. iGlarLixi has proven clinical benefits in terms of glycemia, weight control, and safety, defined by the risk of hypoglycemia. It simultaneously targets many pathophysiologic abnormalities which are at the root of type 2 diabetes and thus presents a complementary mode of action. Finally, it may also address diabetes treatment burden, and, by decreasing the complexity of treatment, it may improve patient adherence and persistence and fight against clinical inertia. This article reviews the results of major randomized controlled trials in people with type 2 diabetes that compared iGlarLixi to other therapeutic regimens, representing different intensification strategies, such as basal supported oral therapy, oral antidiabetic drugs, and a combination of the latter with glucagon-like peptide 1 receptor agonists. Moreover, as a supplement to randomized trials, data from real-world evidence have also been included.

Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes in Adriatic Region Countries: ENSURE-ADR, a Real-World Study.

INTRODUCTION: The efficacy of iGlarLixi, a fixed-ratio combination of basal insulin glargine 100 units/mL (iGlar) and the short-acting GLP-1 RA lixisenatide (Lixi), was established in people with type 2 diabetes (T2D) who were advancing therapy from oral antidiabetic drugs (OADs) and basal insulin (BI). This retrospective study aimed to evaluate the effectiveness and safety of iGlarLixi using real-world data from people with T2D in the Adriatic region countries. METHODS: This was a non-interventional, retrospective, multicenter, cohort study with the collection of pre-existing data at iGlarLixi initiation and after 6 months of treatment in real-world clinical and ambulatory settings. The primary outcome was the change in glycated hemoglobin (HbA1c) at 6 months after iGlarLixi initiation. Key secondary outcomes included the proportion of people achieving HbA1c < 7.0%, the effect of iGlarLixi on fasting plasma glucose (FPG), body weight and body mass index (BMI). RESULTS: In this study, 262 participants (130 in Bosnia and Herzegovina, 72 in Croatia and 60 in Slovenia) initiated treatment with iGlarLixi. The participants had a mean ± SD age of 66.2 ± 7.9 years and the majority were women (58.0%). The mean baseline HbA1c was 8.9 ± 1.7% and the mean body weight was 94.3 ± 18.0 kg. After 6 months of treatment, the reduction in the mean HbA1c was statistically significant (1.11 ± 1.61%, 95% confidence internal [CI] 0.92, 1.31; p < 0.001), and the proportion of participants who achieved HbA1c < 7.0% had significantly increased from baseline (8.0-26.0%, p < 0.001). The change in mean FPG (mmol/L) levels was significant (2.7 ± 4.4 [95% CI 2.1, 3.2; p < 0.001]). The mean ± SD body weight and BMI were significantly reduced by 2.9 ± 4.3 kg (95% CI 2.3, 3.4; p < 0.001) and 1.3 ± 4.4 kg/m2 (95% CI 0.7, 1.8; p < 0.001), respectively. Two serious hypoglycemia episodes and one adverse gastrointestinal effect (nausea) were registered. CONCLUSIONS: This real-world study demonstrated the effectiveness of iGlarLixi for improving glycemic control and decreasing body weight in people with T2D who need to advance therapy from OADs or insulin.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.