Thomas Blevins

Pharmacy benefit managers (PBMs) administer prescription drug benefits for insurers, employers, and other payers through formulary design, rebate negotiation, pharmacy network management, and utilization controls. In diabetes care, cost-containment strategies such as formulary-driven medication switching, step therapy, and formulary exclusivity have increasingly restricted access to essential medications and technologies. These rebate-driven practices often prioritize financial incentives over clinical appropriateness, leading to forced nonmedical switching, higher out-of-pocket costs, reduced adherence, and poorer glycemic outcomes. This narrative review examines how PBM-driven policies undermine patient-centered, evidence-based diabetes care and disrupt continuity of treatment. Greater transparency, preservation of patient and clinician choice, and policies that align PBM incentives with clinical outcomes are needed to reduce harm and improve access to appropriate diabetes therapies.

Background: Technosphere insulin (TI) is an ultra-rapid-acting inhaled insulin approved for glucose management in adults with diabetes mellitus. Using a higher modified initial conversion dose than in the current United States Prescribing Information, this study assessed supplementing or replacing automated insulin delivery (AID) systems with TI. Methods: Adult participants with type 1 diabetes (glycated hemoglobin [HbA1c], 7%-11%) using an AID system were randomized into TI + AID (TI for meals and AID for basal and corrections), TI + insulin degludec (TI for meals and corrections and insulin degludec for basal), or control group (remaining on AID) and treated for 90 days. HbA1c, forced expiratory volume in 1 second (FEV ₁ ), hypoglycemic events, and adverse events (AEs) were assessed. Results: Of 33 enrolled participants, 24 completed the study. All groups demonstrated comparable declines in HbA1c from baseline to end of treatment (statistically significant decline for control group). No within- or between-group statistical differences were observed in FEV ₁ . Incidence and event rate of hypoglycemia <70 mg/dL and <54 mg/dL were similar between groups, and no severe hypoglycemic events were reported. No treatment-related serious AEs were reported, and 2 participants experienced AEs of special interest related to TI (clinically relevant decline in pulmonary function and wheezing). Conclusions: This proof-of-concept study demonstrated the safety and efficacy of TI, at a higher modified dose conversion, when added for mealtime control to an AID system or was used for glycemic control with basal insulin.

Aims: Insulin efsitora alfa (efsitora) is a once‐weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT‐1 through QWINT‐5. Materials and Methods: The five trials included insulin‐naïve adults (QWINT‐1 and ‐2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT‐3 and ‐4), and QWINT‐5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open‐label, treat‐to‐target studies to investigate the efficacy and safety of efsitora versus active once‐daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient‐reported outcome questionnaires. Conclusions: The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.

Background MYL-1601D is a proposed biosimilar of originator insulin aspart, Novolog^®/NovoRapid^® (Ref-InsAsp-US/Ref-InsAsp-EU). Objective This study assessed the immunogenicity, efficacy, and safety of MYL-1601D with Ref-InsAsp-US in patients with type 1 diabetes mellitus (T1D). Methods This was a 24-week, open-label, randomized, phase III study. Patients were randomized 1:1 to mealtime MYL-1601D or Ref-InsAsp-US in combination with insulin glargine (Lantus SoloSTAR^®) once daily. The treatment-emergent antibody response (TEAR) rate (defined as patients who were anti-insulin antibody [AIA] negative at baseline and became positive at any timepoint post-baseline or patients who were AIA positive at baseline and demonstrated a 4-fold increase in titer values at any timepoint post-baseline) was the primary endpoint. The study also compared the change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, 7-point self-monitored blood glucose (SMBG) profiles, immunogenicity, and adverse events (AEs) including hypoglycemia. Results In total, 478 patients were included in the intent-to-treat analysis (MYL-1601D: 238; Ref-InsAsp-US: 240) set. The 90% confidence interval (CI) for the primary endpoint was within the pre-defined equivalence margin of ±11.7% and the treatment differences (SE) in TEAR responders between the treatment groups was − 2.86 (4.16) with 90% CI − 9.71 to 3.99. The mean (SD) changes from baseline for HbA1c, FPG, and insulin dosages were similar in both groups at week 24. The safety profiles including hypoglycemia, immune-related events, AEs, and other reported variables were similar between the treatment groups at week 24. Conclusions MYL-1601D demonstrated similar immunogenicity, efficacy, and safety profiles to Ref-InsAsp-US in patients with T1D over 24 weeks. Clinical Trial Registration ClinicalTrials.gov: NCT03760068.

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Background: The E V aluating U-500R I nfusion V ersus I njection in Type 2 D iabetes Mellitus (VIVID) study compared two methods of U-500R insulin delivery, continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI), for 26 weeks in people with type 2 diabetes (T2D) requiring high doses of insulin. To assess glycemic variability (GV) and time in range (TIR), a subset of participants performed masked continuous glucose monitoring (CGM). Methods: VIVID participants were adults who had insulin requirements of >200 but ≤600 U/day and A1C 7.5% to 12%. Participants performed masked CGM for seven consecutive days on each of three occasions: before weeks 0 (baseline), 14, and 26. The primary objective was to compare GV between CSII and MDI groups, based on change from baseline of within-day standard deviation (SD _w ) of CGM glucose. Results: Of 54 participants enrolled, 41 with evaluable data were analyzed (17 and 24 in CSII and MDI groups, respectively). The CSII group had a significantly greater reduction from baseline in mean SD _w of glucose (45.0 to 38.2 mg/dL [−8.1 mg/dL]) compared with the MDI group (47.0 to 45.8 [−0.4 mg/dL]; P = 0.047). TIR 70–180 mg/dL glucose increased significantly from baseline in the CSII group only, from 59.8% to 73.1% (change +12.9%, P < 0.05), but was not significantly different between groups. There were no significant between-group differences in the endpoint mean glucose or A1C. Conclusions: In the VIVID CGM substudy of U-500R in people with T2D requiring high doses of insulin, participants using CSII significantly reduced GV compared with MDI. CSII also significantly increased TIR with no difference between groups.

Aims MYL‐1501D, recently approved by the European Medicines Agency, is being developed as a biosimilar (European Union) or a follow‐on biologic (United States) to insulin glargine. This study assessed efficacy, insulin dose, safety, and immunogenicity when patients with type 1 diabetes mellitus switched between MYL‐1501D and reference insulin glargine (Lantus®; Sanofi‐Aventis US LLC, Bridgewater, NJ). Materials and methods Eligible patients from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment‐switching sequence (n = 64; MYL‐1501D [weeks 0–12], reference insulin glargine [weeks 12–24], MYL‐1501D [weeks 24–36]). Change in glycated hemoglobin (HbA_1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the 2 treatment sequences. Secondary endpoints included change in fasting plasma glucose (FPG), self‐monitored blood glucose (SMBG), and insulin dose; immunogenicity; and adverse events, including hypoglycemia. Results Mean changes in HbA_1c (least squares [LS] mean [standard error]) from baseline to week 36 were − 0.05 (0.032) and − 0.06 (0.034) for the treatment‐switching and reference sequences, respectively (LS mean difference [95% CI], 0.01 [−0.085, 0.101]). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG, and insulin dose, and the safety and immunogenicity profiles of the 2 sequences were similar. Conclusions Switching patients between MYL‐1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, demonstrating that patients taking reference insulin glargine can safely switch to MYL‐1501D.

Aims Insulin glargine is a long‐acting human insulin analogue that can be administered once daily in patients with type 2 diabetes mellitus (T2DM). MYL‐1501D is a proposed biosimilar or follow‐on biologic to marketed insulin glargine. This study assessed noninferiority of MYL‐1501D to reference insulin glargine (Lantus®; Sanofi‐Aventis US LLC, Bridgewater, NJ) based on change in glycosylated hemoglobin (HbA_1c). Materials and methods INSTRIDE 2 was a multicenter, open‐label, randomized, parallel‐group, phase 3 noninferiority study comparing efficacy and safety of MYL‐1501D with those of reference insulin glargine in insulin‐naive and insulin–non‐naive patients with T2DM receiving oral antidiabetic drugs (OADs). The primary efficacy endpoint was change in HbA_1c from baseline to week 24. Secondary endpoints included metabolic readouts (eg, changes in fasting plasma glucose, insulin dosage, self‐monitored blood glucose), immunogenicity, and adverse events, including hypoglycemia and nocturnal hypoglycemic events. Results In all, 560 patients were randomized to MYL‐1501D or insulin glargine in combination with OADs for 24 weeks. Mean change in HbA_1c from baseline to week 24 was ‐0.60% (95% CI: ‐0.78, ‐0.41) and ‐0.66% (95% CI: ‐0.84, ‐0.48) for MYL‐1501D and reference insulin glargine, respectively. MYL‐1501D was well tolerated and had a safety profile comparable to that of reference insulin glargine. Conclusions Demonstration of noninferiority between MYL‐1501D and reference insulin glargine for reduction of HbA_1c during 24 weeks of treatment was achieved. Both treatment groups were comparable in terms of secondary endpoints, including hypoglycemia and nocturnal hypoglycemia, local and systemic reactions, other safety parameters, and immunogenicity.