In 2021, IDegLira was introduced in China as a treatment option for patients with type 2 diabetes mellitus (T2DM). We aimed to evaluate the long-term cost-utility of IDegLira compared to basal-bolus therapy and glucagon-like peptide-1 receptor agonist (GLP-1RA) added to basal insulin in patients with T2DM who remain uncontrolled on basal insulin in China.

The Swedish Institute for Health Economics (IHE) T2DM Cohort Model was employed to project health and cost outcomes over a 30-year time horizon. Baseline cohort characteristics were derived from the DUAL II China study. Treatment effects were derived from DUAL VII study and a pooled analysis. Costs were considered from a health system perspective in China and expressed in 2023 Chinese yuan (CNY). Health outcomes were measured in quality-adjusted life years (QALYs). Health state utilities were obtained from several published sources. Future costs and clinical outcomes were discounted at an annual rate of 5%.

IDegLira was associated with an improvement of 0.810 QALYs and a cost reduction of CNY 91,217 compared to basal-bolus therapy. Similarly, compared to GLP-1RA added to basal insulin, IDegLira demonstrated a health gain of 0.011 QALYs and a cost reduction of CNY 23,815, establishing IDegLira as the dominant option. The sensitivity analyses indicated a 100% probability of IDegLira being cost-effective.

For T2DM patients who remain uncontrolled on basal insulin, IDegLira was projected to be dominant and could offer better value compared to both basal-bolus therapy and GLP-1RA added to basal insulin in the Chinese setting.

IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).

In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.

Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC0-t: ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (Cmax): 1.12 [1.06; 1.18]. Semaglutide AUC0-t was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide Cmax was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.

The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.

ClinicalTrials.gov identifier: NCT03789578.

To evaluate the efficacy of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) using derived time-in-range (dTIR).

Participant-level data from LixiLan-L, LixiLan-O and LixiLan-G were pooled and dTIR (70-180 mg/dL), derived time-above-range (> 180 mg/dL) and derived time-below-range (dTBR; < 70 mg/dL) were calculated from participant seven-point self-monitored blood glucose profiles.

This pooled analysis included data from 2420 participants receiving iGlarLixi (n = 1093), iGlar (n = 836), Lixi (n = 234) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) (n = 257). Numerically greater improvements in least square (LS) means dTIR were seen from baseline to end of treatment (EOT) with iGlarLixi (25.7%) versus iGlar (15.8%), Lixi (11.7%) or GLP-1 RA (16.2%). At EOT, the mean (standard deviation) dTBR was 0.71% ± 3.4%, 0.61% ± 3.2%, 0.08% ± 1.0% and 0.0% ± 0.0% for iGlarLixi, iGlar, Lixi and GLP-1 RA, respectively. In a subgroup analysis, participants aged younger than 65 years (n = 1690) and 65 years or older (n = 713) showed numerically greater improvements in LS means dTIR from baseline to EOT with iGlarLixi versus iGlar, Lixi or GLP-1 RA.

iGlarLixi achieved improvements in dTIR, with low dTBR values, providing further evidence to inform clinical outcomes with the use of iGlarLixi.

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).

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.

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.

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.

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.

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).

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.

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]).

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.

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).

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).

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.

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.

Fixed ratio combination of insulin degludec and liraglutide (IDegLira) represents an option to revise inappropriate therapies in patients with poorly controlled type 2 diabetes. This study aimed to assess the pattern of use and 1-year effectiveness of IDegLira.

A retrospective chart review was performed to assess changes in glycated hemoglobin (HbA1c) (primary endpoint), fasting blood glucose (FBG), body weight, estimated glomerular filtration rate (eGFR), and lipid profile following IDegLira initiation. Previous versus concomitant diabetes treatments were also compared.

Overall, 87 patients (mean age 73.9 ± 9.2 years, diabetes duration 18.2 ± 6.7 years, 62.1% men, HbA1c 8.3 ± 1.3%, BMI 30.4 ± 5.5 kg/m2) initiated IDegLira. Previously, 21.8% of patients were treated with oral hypoglycemic agents (OHA group), 47.1% with basal insulin ± OHA (BOT group), 5.8% with GLP-1 RA ± basal insulin (GLP1-RA group), and 25.3% with basal-bolus schemes (BB group). At the first prescription of IDegLira, secretagogues and schemes including two or more OHA were substantially reduced, leaving metformin as the most prevalent OHA (81.6%) used in combination with IDegLira. Starting dose of IDegLira ranged from 18.7 ± 3.1 U (OHA group) to 24.1 ± 4.4 U (BB group). After 1 year, HbA1c was significantly reduced by 1.25% (95% CI - 1.48; - 1.03), FBG by 52.9 mg/dl, and body weight by 2.0 kg. Also, eGFR levels and lipid profile significantly improved. No severe hypoglycemia occurred.

It is possible to proactively review suboptimal or inappropriate diabetes treatment according to the most recent guidelines. Results suggest that initiation of IDegLira was associated with a reduction in drugs to be administered daily and relevant improvements in clinical outcomes.

The clinical benefits of treating patients with type 2 diabetes mellitus (T2DM) with fixed-ratio combination of insulin iGlar (iGlar) plus lixisenatide (iGlarLixi) were demonstrated in clinical trials and real-world evidence studies; however, its cost impact to healthcare payers is unknown.

A budget impact model was developed from a United States (US) payer's perspective for a hypothetical healthcare plan of 1 million people over a 1-year time horizon. In scenario analysis, patients with uncontrolled glycated hemoglobin (HbA1c) treated with 60 units or less of daily insulin (insulin cohort) or oral antidiabetic drugs (OADs) only (OAD cohort) were intensified to iGlarLixi/rapid-acting insulin (RAI)/glucagon-like peptide 1 receptor agonists (GLP-1RA) or iGlarLixi/iGlar/GLP-1RA, respectively. Model inputs from real-world data (RWD) included baseline market shares, proportion of patients intensifying to respective treatments, and dosing inputs; unit costs were obtained from published literature. One-way sensitivity analyses assessed the impact of individual parameters.

Intensification with iGlarLixi resulted in the lowest incremental per member per month (PMPM) budget impact compared to other intensifying drugs (iGlar, RAI, and GLP-1RA). In the insulin cohort, the incremental PMPM cost for intensification with iGlarLixi ($0.03) was the lowest among intensifying drugs; GLP-1RA ($72.20) and RAI ($4.81). Similarly, the incremental PMPM cost for intensification with iGlarLixi was the lowest ($1.25) in the OAD cohort among intensifying drugs; GLP-1RA ($321.65) and iGlar ($114.82). In scenario analyses, when equal market intensification shares for iGlarLixi and GLP-1RA were explored, the incremental PMPM cost for iGlarLixi ($0.03) remained lower than GLP-1RA ($2.28) and RAI ($10.44) in the insulin cohort.

Intensification with iGlarLixi was associated with lower costs compared to other treatment intensifications, as well as overall budget reductions compared to pre-intensification when considering cost savings attributable to reduction in HbA1c; therefore, its inclusion for the treatment of T2DM would represent a budget saving.

The aim of the study was to provide real-world data on the effectiveness and safety of a new fixed-ratio combination, insulin degludec/liraglutide (IDegLira) injection in Japanese patients with type 2 diabetes mellitus (T2DM).

The primary endpoint was the change in glycated hemoglobin (HbA1c) level 6 months after the introduction of IDegLira. We also examined the rate of achievement of target HbA1c 7% and the individualized HbA1c targets set for each patient. Baseline characteristics associated with the change in HbA1c were also assessed. Seventy-five patients with T2DM were included in the analysis.

After the initiation of IDegLira, HbA1c decreased significantly from baseline with a change of -1.81% (baseline 9.61% and at 6 months 7.80%; P < 0.001). At baseline, the achievement rate of 7% HbA1c was 2.67% (n = 2), which increased to 36.0% (n = 27) after 6 months of IDegLira introduction (P < 0.05). The attainment rate of individualized HbA1c targets, which were set considering each patient's characteristics, improved from 2.67% (n = 2) to 49.3% (n = 37) (P < 0.001). Regardless of sex, body mass index, estimated glomerular filtration rate, duration of diabetes, or history of glucagon-like peptide-1 receptor agonist use, IDegLira significantly reduced HbA1c, but a higher C-peptide index was associated with a greater reduction in HbA1c.

In this study, initiation of IDegLira in a real-world clinical setting was beneficial in lowering HbA1c in Japanese T2DM patients with inadequate glycemic control with existing therapy.

Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system.

A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA_1c and body weight were determined in patients with available follow-up data (nearest 6-month visit).

IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA_1c were 60.1 ± 10.2 years, 33.4 ± 6.2 kg/m² and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178 days), HbA_1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and - 0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8 kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1 kg, p < 0.0001) while those on BI (- 1.4 ± 4.6 kg, p = 0.0139) or MDI (- 1.4 ± 5.0 kg, p = 0.0484) experienced weight loss.

While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.

To compare the efficacy and safety of a simple daily titration algorithm compared with a weekly dose adjustment of iGlarLixi in people with type 2 diabetes.

LixiLan ONE CAN (NCT03767543), a randomized, 26-week, open-label, multicentre phase 3 trial conducted in Canada, involved 265 people with type 2 diabetes and an HbA1c of ≥7.5% to ≤ 10.5% or less (≥58 to ≤91 mmol/mol) on basal insulin for 6 months or longer. Participants were randomized 1:1 with instructions to self-titrate iGlarLixi daily (1 unit/day) or once weekly (2 or 4 units/week) to a common target fasting plasma glucose of 4.4 to 5.6 mmol/L (79 to 101 mg/dl). The primary objective was to show non-inferiority of the daily versus weekly titration algorithm.

At 26 weeks, daily titration of iGlarLixi was not inferior to a weekly titration for both the prespecified primary endpoint of change in HbA1c from baseline (least square [LS] mean change: -1.24% vs. -0.92%, respectively; LS mean difference: 0.32%; 95% CI [0.07, 0.57]; P < .0001) and for the secondary endpoint of change in weight from baseline (LS mean change: -0.22 vs. +0.81 kg, respectively; LS mean difference: 1.03 kg; 95% CI [0.01, 2.06]; P < .0001). Indeed, for both the primary and secondary outcome, the daily titration of iGlarLixi was superior. There were no statistically significant differences in hypoglycaemia incidence between the two titration strategies during the 26-week study.

A daily titration algorithm for switching basal insulin to iGlarLixi was shown to be non-inferior and superior for glycaemic control and weight compared with weekly titration.

Two fixed-ratio combinations (FRCs) of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) are available for once-daily use in adults with type 2 diabetes. We aimed to review the clinical evidence for the efficacy and safety of changing treatment from a basal-bolus insulin (BBI) regimen or a premix insulin to these combination treatments (fixed-ratio or loose) and provide expert opinion on the practicalities of making such a change.

Relevant clinical and trial evidence and general review articles were identified through a literature review of ProQuest (comprising BIOSIS Previews®, Current Contents® Search, Embase® and MEDLINE®) for articles published between 2009 and 2021.

We identified nine articles reporting the results of FRCs, and seven articles reporting results of loose combinations of basal insulin and GLP-1RAs, in people who transitioned treatment from BBI or premix regimens. In most trials, combination treatment led to improved or equivalent glycaemic control, and a reduction in body weight or BMI, versus the original regimens. Some trials reported a reduction in total insulin dose. A few trials reported reduced or unchanged hypoglycaemia rates, or increased patient satisfaction, with combination therapy where these endpoints were examined. We provide guidance on transitioning of treatment and the patient types most likely to benefit.

In people not achieving glycaemic control with BBI or premix insulin regimens, an FRC or loose combination of basal insulin and GLP-1RA may improve control, decrease the risk of body weight gain or hypoglycaemia and reduce the complexity of treatment.

To assess the effectiveness and safety of insulin glargine and lixisenatide (iGlarLixi) fixed-ratio combination on a cohort of Romanian adults with type 2 diabetes (T2D).

Open-label, 24-week, prospective cohort study.

65 secondary care diabetes centres in Romania.

The study included 901 adults with T2D suboptimally controlled with previous oral antidiabetic drugs (OADs)±basal insulin (BI) who initiated treatment with iGlarLixi upon the decision of the investigator. Major exclusion criteria were iGlarLixi contraindications and refusal to participate. 876 subjects received at least one dose of iGlarLixi (intention-to-treat/safety population).

The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 24 in the modified intention-to-treat population (study participants with HbA1c available at baseline and week 24). Secondary efficacy outcomes were percentage of participants reaching HbA1c targets and change in fasting plasma glucose (FPG).

Mean baseline HbA1c was 9.2% (SD 1.4) and FPG was 10.8 mmol/L (2.9). Mean HbA1c change was -1.3% (95% CI: -1.4% to -1.2%, p<0.0001) at week 24. HbA1c levels ≤6.5%, <7% and<7.5% at week 24 were achieved by 72 (8.9%), 183 (22.6%) and 342 (42.3%) participants, respectively. Mean FPG change was -3.1 mmol/L (95% CI: -3.3 to -2.8, p<0.001) at week 24. Mean body weight change was -1.6 kg (95% CI: -1.9 to -1.3, p<0.001) at 24 weeks. Mean iGlarLixi dose increased from 19.5 U (SD 7.7) and 30.1 U (10.0) to 30.2 U (8.9) (ratio 2/1 pen) and 45.0 U (11.6) (ratio 3/1 pen). Adverse events (AEs) were reported by 43 (4.9%) participants (18 (2.1%) gastrointestinal) with 4 (0.5%) reporting serious AEs. 13 (1.5%) participants reported at least one event of symptomatic hypoglycaemia, with one episode of severe hypoglycaemia reported.

In a real-world setting, 24-week treatment with iGlarLixi provided a significant reduction of HbA1c with body weight loss and low hypoglycaemia risk in T2D suboptimally controlled with OADs±BI treatment.

Given the progressive nature of type 2 diabetes (T2D), most individuals with the disease will ultimately undergo treatment intensification. This usually involves the stepwise addition of a new glucose-lowering agent or switching to a more complex insulin regimen. However, complex treatment regimens can result in an increased risk of hypoglycaemia and high treatment burden, which may impact negatively on both therapeutic adherence and overall quality of life. Individuals with good glycaemic control may also be overtreated with unnecessarily complex regimens. Treatment simplification aims to reduce individual treatment burden, without compromising therapeutic effectiveness or safety. Despite data showing that simplifying therapy can achieve good glycaemic control without negatively impacting on treatment efficacy or safety, it is not always implemented in clinical practice. Current clinical guidelines focus on treatment intensification, rather than simplification. Where simplification is recommended, clear guidance is lacking and mostly focused on treatment of the elderly. An expert, multidisciplinary panel evaluated the current treatment landscape with respect to guidance, published evidence, recommendations and approaches regarding simplification of complex insulin regimens. This article outlines the benefits of treatment simplification and provides practical recommendations on simplifying complex insulin treatment strategies in people with T2D using illustrative cases.

Design of "first-generation" insulin analogues over the past 3 decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool kit-integrating protein sequence, chemical modification, and formulation-has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultrarapid and ultrabasal analogue formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogues seek to exploit therapeutic mechanisms: glucose-responsive ("smart") analogues, pathway-specific ("biased") analogues, and organ-targeted analogues. Smart insulin analogues and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogues may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will affect use and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale, and potential clinical applications.

This study evaluates the efficacy and safety of the free up-titration of basal insulin and fixed-ratio combination (FRC) of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) patients inadequately controlled with GLP-1RA.

With the use of a systematic literature review of PubMed, Embase, Web of Science, and the Cochrane Library databases through July 2021, randomized controlled trials that compared the free up-titration or FRC with remaining on GLP-1RA in T2DM patients uncontrolled with GLP-1RA were included. A comparison of adding basal insulin to maintaining GLP-1RA and an indirect comparison between the two strategies were conducted on the change in HbA1c, fasting plasma glucose (FPG), target achievement [HbA1c < 7.0%], and the risk of confirmed hypoglycemia. The Cochrane Collaboration's tool was used to assess the risk of bias.

Two free up-titration and two FRC trials involving 1,612 participants, all lasting 26 weeks, were included. Both approaches significantly lowered HbA1c levels (weighted mean difference [WMD] -0.75%, 95% CI -0.97 to -0.53) but increased hypoglycemic risk [risk ratio (RR) 7.59, 95% CI 3.35-17.17] compared to the unchanged GLP-1RA. No significant differences were discovered between the two methods regarding the decrease in HbA1c (WMD 0.08%, 95% CI -1.07% to 1.23%), FPG (WMD -2.29 mg/dl, 95% CI -45.07 to 40.49 mg/dl), target achievement (RR 1.03, 95% CI 0.50-2.14), and hypoglycemic risk (RR 0.32, 95% CI 0.03-3.59).

In patients who failed to reach target HbA1c levels despite the GLP-1RA treatment, both strategies of adding basal insulin, free up-titration and FRC, are comparable options are comparable options.

Hypoglycemia is a common complication in patients with diabetes, mainly in those treated with insulin, sulfonylurea, or glinide. Impairments in counterregulatory responses and hypoglycemia unawareness constitute the main risk factors for severe hypoglycemia. Episodes of hypoglycemia are associated with physical and psychological morbidity. The fear of hypoglycemia constitutes a barrier that impairs the patient's ability to reach good glycemic control. To prevent hypoglycemia, much effort must be invested in patient education regarding risk factors, warning signs, and treatment of hypoglycemia at an early stage, together with setting personalized goals for glycemic control. In this review, we present a comprehensive update on the treatment and prevention of hypoglycemia in type 1 and type 2 diabetic patients.

The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding.

Pioneering crystallographic analyses-beginning with Hodgkin's solving of the 2-Zn insulin hexamer-elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia.

Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.

The aim of this study was to elaborate a consensus on treatment intensification strategies in patients with type 2 diabetes failing basal insulin supported oral therapy (BOT). The panel focused on glucagon-like peptide-1 receptor agonists (GLP-1RA) and basal insulin (BI) combinations.

The authors developed a Delphi questionnaire organized into ten statements and 77 items that focused on: the definition of BOT and BOT failure, intensification strategies, fixed-dose combinations in general and the BI/GLP-1RA fixed combination. The survey was administered in two rounds to a panel of 80 Italian diabetes specialists, who rated their level of agreement with each item on a 5-point Likert scale. Consensus was predefined as > 66% of the panel agreeing/disagreeing on any given item.

Consensus was achieved for 71 of the 77 items. The panel agreed that the use of sulfonylureas in the BOT regimen is inappropriate. BOT failure was defined as individualized targets not being met for glycated hemoglobin, fasting plasma glucose and/or postprandial plasma glucose. There was agreement that postprandial hyperglycaemia and/or presence of nocturnal hypoglycaemia or weight gain define BOT failure. Addition of a GLP-1RA to BI therapy was considered to be the best option for BOT intensification. There was consensus for the use of BI/GLP-1RA fixed combinations as valuable options to increase compliance and safely improve glycaemic control. The panel agreed in considering the fixed-ratio combination insulin degludec/liraglutide (IDegLira) to be preferable to the fixed-ratio combination insulin glargine/lixisenatide (iGlarLixi) in the control of glycaemia, body weight and cardiovascular risk.

According to this Delphi consensus, the addition of a GLP-1RA may be the best option to intensify BOT. The BI/GLP-1RA fixed combinations may increase compliance and optimize the advantages of each of these molecules.

Worldwide prevalence of Type 2 Diabetes (T2D) has become a major concern with several implications for public health, economy, and social well-being, especially in developing countries. Conventional pharmacological management of T2D have proved effective, but possess underlying side effects, leading the scientific community to research alternative compounds that exert beneficial effects on current therapeutic targets of T2D. Bioactive peptides (BAPs) from food sources, have shown relative advantages in this matter, moreover, BAPs have proved to impart anti-diabetic activity through one or more mechanisms such as enzymatic inhibition of α-glucosidase, α-amylase and DPP-IV. Several plants and animal have been used as protein sources of anti-diabetic BAPs, in the sense of this matter, the pseudo-cereals amaranth and quinoa, along with the ancestral grain chia, have gained attention. Due, to their high protein content and balanced amino-acid composition, along with proved anti-diabetic features, the three seeds are top choices for the obtention of anti-diabetic BAPs. With a comprehensive overview of the most recent reported in silico and in vitro anti-diabetic studies in relation to biomarkers α-glucosidase, α-amylase and DPP-IV, the present review aims to examine the current knowledge of amaranth, quinoa and chia derived anti-diabetic BAPs and their effects on T2D therapeutic markers.

Many people with diabetes do not achieve individualized treatment targets. Therapeutic inertia, the underuse of effective therapies in preventing serious clinical end points, is a frequent, important contributor to this failure. Clinicians, patients, health systems, payors, and producers of medications, devices, and other products for those with diabetes all play a role in the development of therapeutic inertia and can all help to reduce it.

The aim is to devise a new short-term intensive insulin therapy (N-SIIT) based on the concept of "treat to target" to avoid hypoglycaemia and was applied it to various diabetic state. We determined dosage of 1 basal and 3 bolus "treat" insulin based on "target" blood glucose level and changed each insulin dose by small units (2 units) every day for 2 weeks. We evaluated the effects of N-SIIT in 74 subjects with type 2 diabetes (male 45, female 29, 64.9 ± 16.6 years old, HbA1c 10.4 ± 2.6%). Glargine U300 ("treat") and morning blood glucose level ("target") was significantly correlated with increasing insulin dose and decreasing blood glucose level in day 1-7, indicating that insulin amount was determined by target blood glucose level and lowered next target blood glucose level. Remission rates were 67.3% (Hypoglycaemia rate 5.6 %) in N-SIIT and 47.3% (Hypoglycaemia rate 38.1%) in conventional SIIT. Required amount of insulin would be automatically determined, depending on each patient pathophysiology and life style. This method is pretty simple, flexible and cheap, and provides information about the dynamic pathophysiological alteration of insulin resistance and glucotoxicity from the profile of blood glucose levels and insulin shot.

The combination of basal insulin (BI) and GLP-1 receptor agonists (GLP-1RAs) is a rational and effective therapy for patients with uncontrolled type 2 diabetes (T2D). We compared the effectiveness of fixed and flexible BI/GLP-1RA combinations using routinely accumulated clinical data.

This was a retrospective, multicentre, real-world study concerning T2D patients initiating a fixed or flexible BI/GLP-1RA combination (NCT03959865). The primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight, fasting plasma glucose (FPG) and systolic blood pressure (SBP). Confounding was addressed by propensity score matching (PSM) or multivariable adjustment (MVA).

A total of 609 patients were included in the study, 131 in the fixed group and 478 in the flexible group. The two groups differed in terms of diabetes duration, body weight and concomitant medications. After 5.7 months, observed HbA1c reductions were 0.6% and 0.8%, and body weight reductions were 2.8 kg and 1.2 kg in the flexible and fixed groups, respectively. Following PSM, HbA1c declined similarly in the two groups, whereas reduction in body weight was significantly in favour of the flexible combination. Findings were robust in sensitivity analyses, with the exception that, with MVA, a significantly higher reduction in HbA1c was detected in the fixed group. Final doses of BI were higher in the fixed group, whereas those of GLP-1RA were higher in the flexible group.

In routine specialist care, initiation of the fixed or flexible BI/GLP-1RA combination allowed similar improvement in glycaemic control, but greater weight loss was observed with the flexible combination. This difference reflected dosages of BI and GLP-1RAs.