Basal Insulin Analogues Research Articles

Basal insulin analogues in type 1 diabetes – does one size fit all? Lessons from the HypoDeg trial based on single-patient outcomes

AimsIn the HypoDeg trial, a randomised crossover trial in people with type 1 diabetes prone to nocturnal severe hypoglycaemia, treatment with insulin degludec (IDeg) resulted in significantly reduced rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia compared to insulin glargine U100 (IGlar). We analysed HypoDeg data at a single-patient level to assess the proportion of participants to whom the overall result applied. MethodsPost hoc analysis using single-patient data (n=133) on nocturnal symptomatic hypoglycaemia, all-day severe hypoglycaemia and HbA1c. The outcome was classified as superior with IDeg, superior with IGlar, or similar between treatments for the three outcomes. We also assessed a composite endpoint based on these outcomes to evaluate the overall superior treatment for each participant. ResultsA higher percentage (38%) had IDeg as superior treatment compared to IGlar (15%) for nocturnal symptomatic hypoglycaemia (p < 0.001). There was no difference between the treatments for all-day severe hypoglycaemia or HbA1c. A higher percentage (44%) had a composite endpoint favouring IDeg compared to IGlar (16%) (p < 0.001). ConclusionsThe superiority of IDeg was confirmed in many of the participants. However, a minority had IGlar as superior treatment, underscoring the need for individualised basal insulin therapy in clinical practice.

Icodec ONWARDS: A review of the first once-weekly diabetes treatment for nurse practitioners and physician assistants.

Diabetes management is challenged by the complexity of treatment regimens and the need for frequent injections, affecting patient adherence and quality of life. Insulin icodec, a once-weekly basal insulin analog, represents a significant innovation, potentially simplifying diabetes care and improving outcomes. This review aims to evaluate the safety, efficacy, and clinical implications of insulin icodec for individuals with type 1 and type 2 diabetes, highlighting its potential to affect current treatment paradigms. A review was conducted comparing once-weekly insulin icodec with daily basal insulin analogs using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure transparent reporting of systematic reviews. A search was performed in the following databases: PubMed, Google Scholar, Embase, and ClinicalTrials.gov, focusing on efficacy and safety outcomes. Insulin icodec has demonstrated effective glycemic management and a safety profile comparable to daily basal insulins. Its extended half-life and steady-state glucose-lowering effect have the potential to reduce the burden of daily injections and improve patient adherence. The introduction of once-weekly insulin icodec represents an advancement in diabetes care. For front-line clinicians, this innovation aligns with the need for more straightforward medication regimens. Coupled with continuous glucose monitoring systems, it enables a more personalized and efficient approach to diabetes management, with the potential to improve patient satisfaction and clinical outcomes. This underscores the impact of integrating such advancements into practice, highlighting the role of nurse practitioners and physician assistants in adopting these innovations to optimize patient care.

7636 Once-weekly Insulin Icodec versus Once-daily Long-acting Insulins for Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis

Abstract Disclosure: S.G. Ribeiro: None. M.P. Chavez: None. L.C. Hespanhol: None. A.B. Neto: None. M.D. Gauza: None. E. Paqualotto: None. C.A. Balieiro: None. C.C. Padovese: None. J.R. Sa: None. Background: Insulin icodec is a novel, long-acting, once-weekly basal insulin analog. Its comparative efficacy and safety with basal once-daily insulins in type 2 diabetes mellittus is uncertain. Objective: Evaluate potential efficacy, benefits and risks associated with icodec compared to once-daily basal insulin analogs (degludec or glargine). Methods: We systematically searched PubMed, Cochrane, and Embase for randomized controlled trials (RCTs) published until June 2023 comparing icodec versus long-acting insulin analogs (degludec and glargine) in type 2 diabetes mellitus (T2DM) with at least 12 weeks of follow-up. Binary endpoints were assessed with risk ratios (RRs) and continuous endpoints were compared using weighted mean differences (WMDs), with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD42023452468). Results: A total of seven RCTs and 3,286 patients with T2DM were included, of whom 1,509 (60.6%) received icodec treatment. The follow-up period ranged from 16 to 78 weeks. Compared with once-daily basal insulin analogs, icodec led to a greater improvement in HbA1c (WMD -0.15%; 95% CI -0.21, -0.10; p&amp;lt;0.0001; I²=0%) and time in range (TIR) (WMD 2.83%; 95%CI 0.94; 4.71; p=0.003; I2=22%). Body weight was increased with icodec treatment (WMD 0.78 Kg; 95%CI 0.42, 1.15; p&amp;lt;0.01; I2=86%). There was also a higher rate of injection site reactions (RR 1.89; 95%CI 1.12, 3.18; p=0.016; I²=0%) and nasopharyngitis (RR 1.94; 95%CI 1.11, 3.38; p=0.020; I²=0%) in the icodec group, compared with once-daily regimens. There was no significant difference between groups in fasting plasma glucose. Conclusions: In this meta-analysis of RCTs, insulin icodec led to better control of HbA1c and TIR as compared with once-daily insulin regimens, albeit with increased weight gain and a higher rate of injection site reaction in the Icodec group. Presentation: 6/3/2024

Cost-utility analysis and drug pricing of once-weekly insulin icodec versus once-daily insulin degludec for type 2 diabetes patients treated with basal insulin in China.

Insulin icodec is a first once-weekly administration basal insulin analogue for type 2 diabetes. This study aimed to investigate the price range of icodec for type 2 diabetes in the Chinese market, taking insulin degludec as reference. Long-term health outcomes and costs for icodec and degludec were simulated using the United Kingdom Prospective Diabetes Study Outcomes Model (version 2.1) over 40 years from the Chinese healthcare provider's perspective. The efficacy and safety data were obtained from the ONWARDS 2 trial (Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial). Cost-utility analysis and a binary search were used to investigate the price range of icodec. Sensitivity analyses were performed to verify the robustness of the base-case analysis results. After a 40-year simulation, the quality-adjusted life years (QALY) of icodec and degludec were 10.32 and 10.28 years, respectively. At the initial assumption of the same annual costs of icodec and degludec of $455.40, icodec was the dominant therapy compared with degludec, with higher QALYs and lower total cost. After the binary search, we observed that the annual cost range of icodec was $625.17-$855.25. This cost range was finally adjusted to be $597.66-$736.34 using one-way sensitivity analysis and confirmed using probabilistic sensitivity analysis and scenario analysis. The scenario analysis revealed that the annual cost range of icodec could be $506.70-$736.34 if the price of degludec decreased by 20% in the future. Insulin icodec appears to be more cost effective than degludec if the annual cost of icodec ranges from $597.66 to $736.34 for patients with type 2 diabetes in China.

Insulin Icodec: First Approval.

Insulin icodec (AWIQLI®) is an ultra-long-acting basal insulin analogue that is being developed by Novo Nordisk for the treatment of diabetes mellitus. Administered once weekly as a subcutaneous injection, insulin icodec is designed to improve treatment adherence and glycaemic control relative to once-daily insulin analogues. On 7 March 2024, insulin icodec was approved in Switzerland for the treatment of diabetes mellitus in adults. Insulin icodec was approved in Canada on 12 March 2024 for the once-weekly treatment of adults with diabetes mellitus to improve glycaemic control and received EU approval in May 2024 for the treatment of diabetes mellitus in adults. This article summarizes the milestones in the development of insulin icodec leading to this first approval for diabetes mellitus.

Once-weekly insulin icodec compared with daily basal insulin analogues in type 2 diabetes: Participant-level meta-analysis of the ONWARDS 1-5 trials.

To perform a participant-level post hoc meta-analysis of Phase 3a trials in type 2 diabetes (T2D) to characterize the hypoglycaemia safety and glycaemic efficacy of once-weekly insulin icodec (icodec). All ONWARDS 1-5 randomized participants were pooled as overall T2D, insulin-naive, an insulin-experienced subgroups, and by once-daily trial comparator (degludec or glargine U100). The main outcomes included incidence and rates of clinically significant and severe hypoglycaemia. Additional endpoints included change in glycated haemoglobin (HbA1c) from baseline and HbA1c target achievement without clinically significant or severe hypoglycaemia. The meta-analysis comprised 3765 participants (1882 icodec vs. 1883 comparators). In the overall T2D pool, clinically significant hypoglycaemia incidence was similar in the icodec group versus the comparator group (17.9% vs. 16.2%, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.94, 1.38); however, rates were low but significantly higher in the icodec group (1.15 vs. 1.00 episodes/participant-year of exposure, estimated rate ratio 1.51 [95% CI 1.24, 1.85]). Fewer severe hypoglycaemic episodes occurred with icodec than with comparators (8 vs. 18). A greater reduction in HbA1c occurred with icodec versus comparators, irrespective of subgroup (estimated treatment difference range [-0.10 to -0.29%]; all p < 0.05). Across subgroups, except for the insulin-experienced subgroup, the odds of achieving HbA1c <53 mmol/mol (7.0%) without clinically significant or severe hypoglycaemia were greater with icodec than with comparators (OR range 1.30-1.55; all p < 0.05). Icodec was associated with a similar incidence but higher rates of clinically significant hypoglycaemia (equating to one additional hypoglycaemic episode every 6 years) and fewer severe hypoglycaemic episodes versus comparators. Our findings also confirmed the greater efficacy of icodec that was demonstrated in the ONWARDS trial programme.

Once-weekly insulin icodec versus once-daily long-acting insulins for type 2 diabetes mellitus: Systematic review and meta-analysis

BackgroundInsulin icodec is a novel, long-acting, once-weekly basal insulin analog. Its comparative efficacy and safety with basal once-daily insulins in type 2 diabetes mellittus is uncertain. ObjectiveEvaluate potential efficacy, benefits and risks associated with icodec compared to once-daily basal insulin analogs (degludec or glargine). MethodsWe systematically searched PubMed, Cochrane, and Embase for randomized controlled trials (RCTs) published until June 2023 comparing icodec versus long-acting insulin analogs (degludec and glargine) in type 2 diabetes mellitus (T2DM) with at least 12 weeks of follow-up. Binary endpoints were assessed with risk ratios (RRs) and continuous endpoints were compared using mean differences (MDs), with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD42023452468). ResultsA total of seven RCTs and 3286 patients with T2DM were included, of whom 1509 (60.6%) received icodec treatment. The follow-up period ranged from 16 to 78 weeks. Compared with once-daily basal insulin analogs, icodec led to a greater improvement in HbA1c (MD -0.15%; 95% CI -0.21, −0.10; p < 0.0001; I2 = 0%) and time in range (TIR) (MD 2.83%; 95%CI 0.94; 4.71; p = 0.003; I2 = 22%). Body weight was increased with icodec treatment (MD 0.78 Kg; 95%CI 0.42, 1.15; p < 0.01; I2 = 86%). There was also a higher rate of injection site reactions (RR 1.89; 95%CI 1.12, 3.18; p = 0.016; I2 = 0%) and nasopharyngitis (RR 1.94; 95%CI 1.11, 3.38; p = 0.020; I2 = 0%) in the icodec group, compared with once-daily regimens. There was no significant difference between groups in fasting plasma glucose. ConclusionsIn this meta-analysis of RCTs, insulin icodec led to better control of HbA1c and TIR as compared with once-daily insulin regimens, albeit with increased weight gain and a higher rate of injection site reaction in the Icodec group.

Which Diabetes Patients Will Benefit the Most from Once-Weekly Basal Insulin Analogs? A Review with a Special Focus on Type 1 Diabetes Patients

Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient’s circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec’s efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (&gt;180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose &lt; 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management.

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

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 asubstantial 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 100U/ml and a GLP-1 RA lixisenatide. 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. 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. ClinicalTrials.gov, identifier NCT04945070.

Expert Opinion on Current Trends in the Use of Insulin in the Management of People with Type 2 Diabetes from the South-Eastern European Region and Israel.

Despite the availability of various antihyperglycaemic therapies and comprehensive guidelines, glycaemic control in diabetes management has not improved significantly during the last decade in the real-world clinical setting. Treatment inertia arising from a complex interplay among patient-, clinician- and healthcare-system-related factors is the prime reason for this suboptimal glycaemic control. Also, the key factor leading to inadequate glycaemic levels remains limited communication between healthcare professionals (HCPs) and people with type 2 diabetes (PwT2D). Early insulin administration has several advantages including reduced glucotoxicity, high efficacy and preserved β-cell mass/function, leading to lowering the risk of diabetes complications. The current publication is based on consensus of experts from the South-Eastern European region and Israel who reviewed the existing evidence and guidelines for the treatment of PwT2D. Herein, the experts emphasised the timely use of insulin, preferably second-generation basal insulin (BI) analogues and intensification using basal-plus therapy, as the most-potent glucose-lowering treatment choice in the real-world clinical setting. Despite an increase in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the experts urged timely insulin initiation for inadequate glycaemic control in PwT2D. Furthermore, the combination of BI and GLP-1 RA addressing both fasting plasma glucose and post-prandial excursions as a free- or fixed-ratio combination was identified to reduce treatment complexity and burden. To minimise discontinuation and improve adherence, the experts reiterated quality, regular interactions and discussions between HCPs and PwT2D/carers for their involvement in the diabetes management decision-making process. Clinicians and HCPs should consider the opinions of the experts in accordance with the most recent recommendations for diabetes management.

Insulin Degludec in People with Type2 Diabetes in China: A Non-interventional, Retrospective Chart Review Study (CN-TREAT).

Insulin degludec (degludec), an ultra-long-acting basal insulin analogue, provides equivalent glycemic control to other basal insulin analogues, with lower risk of hypoglycemia and flexible dosing. Chinese TREsiba AudiT (CN-TREAT) investigated outcomes with degludec in people with type2 diabetes (T2D) in routine clinical practice in China. This was a retrospective chart review study in adults with T2D initiating or switching to degludec at 50 sites in China between January 2020 and July 2021. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study (EOS; week20). Secondary endpoints included change from baseline to EOS in fasting plasma glucose (FPG), self-measured plasma glucose (SMPG), daily insulin dose, and rate of hypoglycemia. Data from 936 participants were included (499 insulin-naïve; 437 insulin-experienced). Mean (95% confidence interval [CI]) HbA1c change from baseline to EOS was - 1.48%-points (- 1.57; - 1.38; P < 0.0001) overall: - 1.95%-points (- 2.08; - 1.81; P < 0.0001) in insulin-naïve participants and - 0.95%-points (- 1.08; - 0.82; P < 0.0001) in insulin-experienced participants. Mean (95%CI) changes in FPG and SMPG were - 2.27mmol/L (- 2.69; - 1.85; P < 0.0001) and - 2.89mmol/L (- 3.52; - 2.25; P < 0.0001), respectively, with similar reductions in insulin-naïve and insulin-experienced subgroups. Rate of hypoglycemia did not change statistically significantly from baseline to EOS overall, or in insulin-experienced participants, except when adjusted for baseline hypoglycemia. Basal insulin dose did not change statistically significantly in insulin-experienced participants. In routine clinical practice in China, initiation or switching to degludec was associated with improvements in glycemic control in people with T2D, with no increased risk of hypoglycemia. ClinialTrials.gov, NCT04227431.

Se-Glargine: Chemical Synthesis of a Basal Insulin Analogue Stabilized by an Internal Diselenide Bridge.

Insulin has long provided a model for studies of protein folding and stability, enabling enhanced treatment of diabetes mellitus via analogue design. We describe the chemical synthesis of a basal insulin analogue stabilized by substitution of an internal cystine (A6-A11) by a diselenide bridge. The studies focused on insulin glargine (formulated as Lantus® and Toujeo®; Sanofi). Prepared at pH 4 in the presence of zinc ions, glargine exhibits a shifted isoelectric point due to a basic B chain extension (ArgB31 -ArgB32 ). Subcutaneous injection leads to pH-dependent precipitation of a long-lived depot. Pairwise substitution of CysA6 and CysA11 by selenocysteine was effected by solid-phase peptide synthesis; the modified A chain also contained substitution of AsnA21 by Gly, circumventing acid-catalyzed deamidation. Although chain combination of native glargine yielded negligible product, in accordance with previous synthetic studies, the pairwise selenocysteine substitution partially rescued this reaction: substantial product was obtained through repeated combination, yielding a stabilized insulin analogue. This strategy thus exploited both (a) the unique redox properties of selenocysteine in protein folding and (b) favorable packing of an internal diselenide bridge in the native state, once achieved. Such rational optimization of protein folding and stability may be generalizable to diverse disulfide-stabilized proteins of therapeutic interest.

Trends in clinical characteristics, medication use, and glycemic control in insulin-treated patients with type 1 and type 2 diabetes in Finland in 2012-2019: Nationwide real-world evidence study.

To describe the clinical characteristics and medication purchases of insulin-treated adults in Finland at index (January 1, 2012 or first insulin purchase) and December 31, 2019. Additionally, to describe basal insulin (BI) treatment patterns and associated changes in hemoglobin A1c (HbA1c) values. In this descriptive study using nationwide registries, we included adults with at least two reimbursed insulin purchases within 12 months of the first purchase between January 1, 2012 and December 31, 2019. We formed four study groups: type 1 diabetes (T1D) and type 2 diabetes (T2D)-diagnosed people who were further divided into prevalent or naïve users (start of insulin use before or after January 1, 2012). Insulin treatment patterns were estimated from medication purchase data and glycemic control from HbA1c results. Out of 145 020 people included, 34 359 had T1D and 110 661 T2D. By 2019, in parallel with the adaptation of new noninsulin medications, second-generation basal insulin (BI) analogues were adopted by 45.9% and 21.1% of prevalent T1D and T2D users. At index, HbA1c target (≤53 mmol/mol) was reached by 17% and 35% of T2D naïve and prevalent users, respectively, and by 17% of T1D prevalent users. At study end, the target was reached respectively by 41%, 34%, and 22% of insulin users. Insulin initiation improved and discontinuation worsened glycemic control in T2D, with lesser effects seen after treatment gaps or switches between BIs. Our study showed that glycemic control in insulin users has remained stable or improved between 2012 and 2019 despite aging population and in parallel with introduction of new treatment options, providing valuable insight into Finnish national diabetes care.

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa.

Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.

The role of basal insulins in the treatment of people with type 2 diabetes and chronic kidney disease: A narrative review.

The majority of cases of chronic kidney disease (CKD) worldwide are driven by the presence of type 2 diabetes (T2D), resulting in an increase in CKD rates over the past few decades. The existence of CKD alongside diabetes is associated with increased burden of cardiovascular disease and increased risk of death. Optimal glycaemic control is essential to prevent progression of CKD, but achieving glycaemic targets in people with CKD and diabetes can be challenging because of increased risk of hypoglycaemia and limitations on glucose-lowering therapeutic options. This review considers the challenges in management of T2D in people with impaired kidney function and assesses evidence for use of basal insulin analogues in people with CKD.

In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk.

Bajaj HS, Aberle J, Davies M, et al. Once-weekly insulin icodec with dosing guide app versus once-daily basal insulin analogues in insulin-naive type 2 diabetes (ONWARDS 5): a randomized trial. Ann Intern Med. 2023;176:1476-1485. 37748181.

Once-weekly Insulin Icodec Versus Once-daily Long-acting Insulin for Type II Diabetes: A Meta-analysis of Randomized Controlled Trials.

Insulin icodec is a novel basal insulin analog with once-weekly subcutaneous administration. We aim to estimate the efficacy and safety of insulin icodec vs long-acting insulin (insulin glargine and degludec) in type II diabetic patients. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, SCOPUS, and Cochrane through May 29, 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI). Our primary outcome was glycated hemoglobin (HbA1C) change. We included 7 RCTs with a total of 3183 patients. Insulin icodec was associated with significantly decreased HbA1C (MD: -0.15 with 95% CI [-0.24, -0.06], P = .002) and increased percentage of time with glucose in range (TIR) (MD: 4.06 with 95% CI [2.06, 6.06], P = .0001). However, insulin icodec was associated with increased body weight (MD: 0.57 with 95% CI [0.45, 0.70], P = .00001). Also, there was no difference regarding any serious adverse events (AEs) (RR: 0.96 with 95% CI [0.76, 1.20], P = .7) or AEs leading to withdrawal (RR: 1.54 with 95% CI [0.84, 2.82], P = .16). However, insulin icodec was associated with increased any AEs incidence (RR: 1.06 with 95% CI [1.01, 1.12], P = .02). Insulin icodec was associated with decreased HbA1C, increased TIR, with similar hypoglycemic and serious AEs. However, it was also associated with increased body weight and the incidence of any AEs.

Once-weekly Insulin Icodec as Compared to Once-daily Basal Insulins: A Meta-analysis

BackgroundOnce-weekly basal insulin icodec has been tested in clinical trials for efficacy and safety over currently available glargine-100 and degludec in different clinical settings for type 2 diabetes. We performed this meta-analysis to evaluate its overall safety and efficacy as compared to glargine-100 and degludec (nonicodec), from all available randomized controlled trials. MethodsSeven trials comparing once-daily basal insulin analogs to once-weekly basal insulin icodec were included. Based on available information, outcomes in terms of HbA1c, fasting plasma glucose reduction, and increase in time in range (TIR) were compared. Side-effects were compared for overall hypoglycemia, severe hypoglycemia, and weight gain. The pooled effect size for continuously distributed data was measured as a reduction in “estimated differences in mean (with 95% CI).” For categorical data, the pooled effect size was measured as the Mantel-Haenszel risk ratio (with 95% CI). ResultsAnalyzing against the nonicodec comparators together, the “estimated mean changes” in HbA1c and fasting plasma glucose favoring icodec were −0.22% (−0.35, −0.10) and −1.59 mg% (−9.26, 6.08) respectively. The “estimated mean increment” in weight for icodec was 0.64 kg (0.61, 0.67). The “estimated mean percentage” increment in TIR for icodec was 4.24% (2.99, 5.49). The Mantel-Haenszel risk ratios for all hypoglycemic events and severe hypoglycemia for icodec were 1.24 (1.02, 1.50) (P = .03) and 0.81 (0.31, 2.08) (P is not significant), respectively, suggesting a 24% increased incidence of all hypoglycemia with icodec. ConclusionOnce-weekly basal insulin icodec as compared to once-daily basal insulin analogs had a slight increase in the risk of overall hypoglycemia and weight gain, without any difference in severe hypoglycemia, with similar glycemic control (in terms of fasting plasma glucose, HbA1c, and TIR).

Clinical Evidence and Practice-Based Guidelines on the Utility of Basal Insulin Combined Oral Therapy (Metformin and Glimepiride) in the Current Era.

Basal insulin combined oral therapy consisting of insulin and oral anti-diabetic drugs (OADs) is recommended for type 2 diabetes uncontrolled on OADs. There is a lack of clear evidence and recommendations on the combined use of basal insulin analogues to more than one OADs (glimepiride plus metformin) in effective control of glycemic parameters and its safety in terms of reduced hypoglycemic events, weight gain and cardiovascular risk. In this context, a group of clinical experts discussed the utility of basal insulin combined oral therapy with metformin and glimepiride in the current era. The clinical experts discussed and provided their inputs virtually. The expert panel included clinical experts comprising endocrinologists and diabetologists from India and Nepal. The panel thoroughly reviewed existing literature on the subject and proposed clinical evidence and practice-based guidelines. These current clinical practice guidelines highlight the efficacy and safety of basal insulin combination therapy with various available basal insulins including neutral protamine hagedorn, detemir, glargine and degludec in addition to metformin and glimepiride therapy.

Efficacy and safety of once-weekly versus once-daily basal insulin analogues in the treatment of type 2 diabetes mellitus: A systematic review and meta-analysis.

To summarize the evidence of recently published randomized controlled trials (RCTs) studying efficacy, in terms of glycaemic control, and safety of the newly developed once-weekly basal insulin analogues. A systematic literature search was conducted through Medline (via PubMed), Cochrane Library and Google Scholar until June 30, 2023. Double-independent study selection, data extraction and quality assessment were performed. Results were summarized with random-effects meta-analysis. A total of 3962 patients with type 2 diabetes mellitus (T2DM) among nine RCTs were analysed. All RCTs had low risk of bias according to the Cochrane Collaboration risk-of-bias tool (RoB2). Once-weekly insulins demonstrated better efficacy in glycated haemoglobin (HbA1c) reduction (mean difference [MD] -0.13%, 95% confidence interval [CI] -0.23, -0.03; P = 0.08) and a significantly greater time in range compared with once-daily insulin analogues (MD 3.54%, 95% CI 1.56, 5.53; P = 0.005). Based on subgroup analyses, the reduction in HbA1c and the odds of achieving an end-of-treatment HbA1c <6.5% were significantly greater for icodec compared to the once-daily insulin (MD -0.18%, 95% CI -0.27, -0.09 [P < 0.001] and odds ratio [OR] 1.75, 95% CI 1.34, 2.29 [P < 0.001], respectively). Once-weekly insulins were associated with higher odds of level 1 hypoglycaemia during the 24-hour period (OR 1.3, 95% CI 1.04, 1.64; P = 0.02) but were safer in terms of level 2 or 3 nocturnal hypoglycaemic events (OR 0.74, 95% CI 0.56, 0.97; P = 0.03). No difference was observed regarding serious adverse events between the two groups. The once-weekly basal insulin analogues seem to be at least equally efficient in glycaemic management and safe compared to once-daily injections in people with T2DM. Phase 4 RCTs are expected to shed further light on the effectiveness and safety of once-weekly insulin therapy over the long term.