ImportanceAngiotensinogen is the most upstream precursor of the renin–angiotensin–aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis.ObjectiveTo evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.Design, Setting, and ParticipantsThis phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized.InterventionsRandomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.Main Outcomes and MeasuresThe primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP.ResultsOf 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were −7.3 mm Hg (95% CI, −10.3 to −4.4) with zilebesiran, 150 mg, once every 6 months; −10.0 mm Hg (95% CI, −12.0 to −7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; −8.9 mm Hg (95% CI, −11.9 to −6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were −14.1 mm Hg (95% CI, −19.2 to −9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; −16.7 mm Hg (95% CI, −21.2 to −12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and −15.7 mm Hg (95% CI, −20.8 to −10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients.Conclusions and RelevanceIn adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.Trial RegistrationClinicalTrials.gov Identifier: NCT04936035

AimsTo summarize the results of clinical studies of insulin icodec, an investigational insulin analog designed for once-weekly administration, in adults with type 1 and type 2 diabetes.MethodsThirteen published articles describing clinical studies of insulin icodec were identified in PubMed, and data pertinent to key study outcomes were selected for inclusion in this review.ResultsIn insulin-na & iuml;ve and insulin-treated individuals, icodec demonstrated efficacy in glycaemic control superior or noninferior to that of insulins glargine U100, glargine U300 and degludec. Icodec exhibited a safety profile comparable to marketed insulins, with the exception of hypoglycaemic event rates.ConclusionsAs a once-weekly alternative to daily basal insulin, icodec is expected to improve patient adherence and satisfaction, reducing the required number of injections per year from 365 to 52 and providing a dosing option potentially attractive to a wide range of insulin users. However, clinical data suggest a notable risk of hypoglycaemia with weekly icodec administration, especially in individuals with type 1 diabetes.

Icosapent ethyl (IPE) was the first fish oil product the US Food and Drug Administration (FDA) approved to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults. IPE is an esterified version of eicosapentaenoic acid (EPA) and acts as a prodrug in the body to exert its effects. IPE affects the body primarily through triglyceride (TG) reduction and was initially indicated for hypertriglyceridemia in addition to statin therapy or for patients with statin intolerances. Various studies have investigated this agent, and multiple subanalyses have been conducted since the FDA approval. These subanalyses have assessed factors such as sex, statin therapy, high-sensitivity C-reactive protein levels (hs-CRP), and various inflammatory biomarkers in groups of patients taking IPE. This article aims to provide a critical review of the clinical data available regarding cardiovascular benefits of IPE in patients with ASCVD and its value as a treatment option for patients with elevated TG levels.

Type 2 diabetes mellitus is a chronic disease most often characterized by increased glucose levels. When blood glucose levels are inadequately controlled or left untreated, the result is a variety of microvascular and macrovascular complications. To prevent these outcomes, many medications are available to manage type 2 diabetes mellitus and prevent disease progression. However, most of the medications available to date only target a few of the physiological defects caused by diabetes and may come with side effects that make adherence to the medication improbable. Imeglimin, a medication currently under investigation in the United States and approved in Japan, is a novel, first-in-its-class medication with a mechanism that is currently understood to target multiple pathways to provide glycemic control. This review aims to present and discuss the current clinical and scientific evidence pertaining to imeglimin.

Abstract Introduction: Increasing insulin prices have led to a renewed debate to determine if Rapid Acting Insulin (RAI) analogs offer an advantage over less expensive Regular Human Insulins (RHI). The steep increase in the cost of RAI has led to rationing of insulin or the total discontinuance of therapy by many patients due to cost. For many, RHI provides a more affordable option for insulin therapy when compared to RAI, especially if the limitations of the insulin profile can be overcome by delivering RHI through continuous subcutaneous insulin infusion (CSII) using a wearable insulin delivery device. To our knowledge, no data exists in a type 2 diabetes (T2D) population comparing RAI to RHI when delivered via CSII. Methods: This 14 week multi-center prospective, randomized parallel, non-inferiority study in a T2D population compared the efficacy and safety of RAI versus RHI when delivered by V-Go®, a 24-hr wearable patch-like insulin delivery device that provides a preset continuous basal rate of insulin and on-demand bolus dosing. This study was conducted in a real-world practice setting under usual standard of care. Glucose lowering agents were to remain stable unless removal warranted due to documented clinically significant hypoglycemia and the only specific guidance for insulin titration was to down-titrate if blood glucose levels were consistently lower than target range. Patients administering RAI with V-Go were randomized 1:1 to continue RAI or to switch to RHI. Primary endpoint assessed non-inferiority for the between group net difference in HbA1c derived from a mixed model analysis. Between group differences from baseline for insulin total daily dose (TDD) and hypoglycemia (based on 7 point glucose profiles) were evaluated as secondary endpoints. Results: One hundred thirteen patients (59 RHI and 54 RAI) were evaluated. Baseline characteristics were similar between cohorts. The mean change in HbA1c with RHI was -0.60% from a baseline of 8.41% vs -0.38% from a baseline of 8.33% with RAI (estimated treatment difference [ETD]: -0.22%; 95% confidence interval [CI] -0.67% to 0.22%; non-inferiority margin<0.4% and p=0.007). The mean change in TDD with RHI was 0.8 U/day from a baseline of 61.0 U/day vs 1.8 U/day from a baseline of 61.3 U/day with RAI (ETD: -1.04 U/day; 95% CI: -3.18 U/day to 1.11 U/day; p=0.92). The absolute change in percent of patients reporting hypoglycemia (≤ 70 mg/dL) from pre-randomization to post-randomization was +5.08% with RHI vs + 5.56% with RAI (ETD: -0.48%; 95% CI: -10.6% to 9.1%; p=0.91). Severe hypoglycemia was not reported in either cohort. Conclusion: Patients with T2D administering RAI with V-Go can safely switch to RHI maintaining similar glycemic control.

Hypoglycemia was evaluated in a 14-week multi-center randomized, parallel, non-inferiority study comparing the efficacy and safety of Rapid Acting Insulin (RAI) versus Human Regular Insulin (HRI) when delivered by V-Go. Glucose lowering agents were to remain stable unless hypoglycemia warranted removal and down-titration of insulin was recommended if glucose levels were consistently lower than target range. Patients were instructed to self-monitor blood glucose (SMBG) daily and perform 7-point SMBG profiles within 3 days of each study visit. Hypoglycemia was defined as: Level 1: ≤70 mg/dl; Level 2: ≤54 mg/dl; and Level 3: severe cognitive impairment requiring external assistance for recovery. The intent to treat population (ITT) consisted of 136 patients randomized to continue treatment with RAI (n=67) or switch to HRI (n=69). Percentages of hypoglycaemia events were similar between groups when comparing pre to post-randomization and the between group difference was not significant. Post-randomization hypoglycemic event rate/person week decreased in both groups compared to pre-randomization. No level 3 events were reported in either group. The incident rate ratio (IRR) was not significant at any level. This study demonstrates the risk of hypoglycemia is not increased when using HRI compared to RAI in V-Go in a T2D population. Disclosure P.F. Mora: Speaker’s Bureau; Self; Dexcom, Inc., Insulet Corporation, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi US, Valeritas, Inc. D.R. Sutton: Employee; Spouse/Partner; Valeritas, Inc. Speaker’s Bureau; Self; Amarin Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Valeritas, Inc. A. Gore: Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc. Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc. Consultant; Self; Novo Nordisk Inc. Speaker’s Bureau; Spouse/Partner; Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc. B. Baliga: Speaker’s Bureau; Self; Amarin Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Senseonics, Valeritas, Inc. R.F. Goldfaden: None. C.C. Nikkel: Employee; Self; Valeritas, Inc. Stock/Shareholder; Self; Valeritas, Inc. J.H. Sink: Employee; Self; Valeritas, Inc. B.A. Adams-Huet: Consultant; Self; Valeritas, Inc. Funding Valeritas, Inc.

The price of insulin has risen substantially and been associated with higher out-of-pocket costs and quicker entry into the Medicare coverage gap, negatively impacting diabetes care in older adults. Evidence from a large health plan supports Human Regular Insulin (HRI), when used effectively, as a viable treatment option for many patients with T2D including older adults. In a recently completed multi-site, 14-week randomized, parallel, study (N=113), non-inferiority was demonstrated when switching from Rapid Acting Insulin (RAI) to HRI delivered by V-Go with a mean change ETD in A1C of -0.22% (95% CI -0.67, 0.22); p=0.007 favoring HRI and no statistical differences in insulin dose, weight or hypoglycemia. We explored these outcomes using mixed-effects models in a post-hoc analysis in pts ≥ 65 years of age. The intent to treat population consisted of 53 pts randomized to continue therapy with RAI (n=25) or switch to HRI (n=28). Non-inferiority for change in A1C between groups was demonstrated in this population. Insulin dose and hypoglycemia events were similar between groups. No severe hypoglycemia or moderate or severe adverse events were reported in either group. Similar to the overall study findings, use of HRI delivered by V-Go is an effective insulin therapy option in an older population and may decrease financial burdens. Disclosure D.R. Sutton: Employee; Spouse/Partner; Valeritas, Inc. Speaker’s Bureau; Self; Amarin Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Valeritas, Inc. P.F. Mora: Speaker’s Bureau; Self; Dexcom, Inc., Insulet Corporation, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi US, Valeritas, Inc. A. Gore: Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc. Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc. Consultant; Self; Novo Nordisk Inc. Speaker’s Bureau; Spouse/Partner; Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc. B. Baliga: Speaker’s Bureau; Self; Amarin Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Senseonics, Valeritas, Inc. R.F. Goldfaden: None. C.C. Nikkel: Employee; Self; Valeritas, Inc. Stock/Shareholder; Self; Valeritas, Inc. J.H. Sink: Employee; Self; Valeritas, Inc. B.A. Adams-Huet: Consultant; Self; Valeritas, Inc. Funding Valeritas, Inc.

OBJECTIVE Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal-bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76). CONCLUSIONS The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.