Alexander Abitbol

Persons carrying loss-of-function variants of proprotein convertase subtilisin-kexin type 9 (PCSK9) have reduced levels of low-density lipoprotein (LDL) cholesterol and fewer atherosclerotic cardiovascular disease events than persons without such variants. VERVE-102 is an investigational base-editing therapy designed to durably inactivate PCSK9 in the liver. In this phase 1, open-label, single-ascending-dose study, we administered one intravenous infusion of VERVE-102 at one of six doses (ranging from 0.3 to 1.0 mg of total RNA per kilogram of body weight [mg per kilogram]) to adults with heterozygous familial hypercholesterolemia or premature coronary artery disease. VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting PCSK9, which are encapsulated in a lipid nanoparticle incorporating N-acetylgalactosamine. The objectives were to assess safety and changes in blood PCSK9 protein and LDL cholesterol levels. A total of 35 participants across the six dose cohorts received VERVE-102 and had at least 28 days of follow-up. No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease. Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose. Corresponding reductions in the LDL cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose. Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants. One dose of VERVE-102 led to dose-dependent, substantial, and sustained reductions in PCSK9 and LDL cholesterol levels. (Funded by Verve Therapeutics; ClinicalTrials.gov number, NCT06164730.).

Aims/hypothesis The aim of this study was to determine the effect of a novel somatostatin receptor 2 (SSTR2) antagonist, ZT-01, on impaired glucagon counterregulation in hypoglycaemia and its safety in adults with type 1 diabetes. Methods In a randomised crossover phase 1b single-site study, blinded to both participants and researchers, participants, aged 18–65 years with BMI 18.5–27 kg/m² with type 1 diabetes (HbA_1c 42.1–74.9 mmol/mol and C-peptide <200 pmol/l) underwent three separate hyperinsulinaemic euglycaemic–hypoglycaemic clamps. Participants were randomised, by a third party, in equal proportion to treatment order with placebo, 3 mg ZT-01 or 20 mg ZT-01 administered subcutaneously during euglycaemia (plasma glucose target 5.0 mmol/l), and exposed to level 1 (target 3.5 mmol/l) and level 2 (target 2.6 mmol/l) hypoglycaemia induced with variable-rate insulin infusion without addition of dextrose. Glucagon response was the primary endpoint; plasma glucose, other counterregulatory hormones, symptom scores and safety were also determined. Results Twenty-four randomised participants (9 female and 15 male) received at least one administration of placebo or ZT-01 and were included for safety analysis. Twenty-two participants completed at least one glucose clamp and were included for pharmacodynamics analysis. Transient increases in plasma glucagon were observed with ZT-01 administration (by 25.7 ± 2.4 ng/l with 3 mg ZT-01 and by 28.4 ± 2.4 ng/l with 20 mg ZT-01), with levels declining to near the pre-dose values before the start of the level 1 hypoglycaemic period. Mean glucagon levels rose again over baseline in both ZT-01 treatment arms during level 1 (by 15.6 ± 2.3 pg/l with 3 mg ZT-01 and by 14.9 ± 2.4 pg/l with 20 mg ZT-01) and level 2 (by 22.8 ± 2.7 pg/l with 3.0 mg ZT-01 and by 29.6 ± 2.8 pg/l with 20 mg ZT-01) hypoglycaemia. With placebo, glucagon levels were unchanged following dosing and during level 1 hypoglycaemia but rose modestly during level 2 hypoglycaemia (by 8.9 ± 2.5 ng/l). Both frequency and amplitude of the increases in glucagon were higher with ZT-01 vs placebo during level 1 and level 2 hypoglycaemia. There were no drug treatment-related adverse events. Conclusions/interpretation Administration of the SSTR2 antagonist ZT-01 increased glucagon responsiveness during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Trial registration ClinicalTrials.gov NCT05007977 Graphical Abstract The alternative text for this image may have been generated using AI.

Background: Co-administration of AS01E-adjuvanted respiratory syncytial virus vaccine (adjuvanted RSVPreF3) and AS01B-adjuvanted recombinant herpes zoster subunit vaccine (RZV), although not contraindicated, has not been previously studied in clinical trials. Methods: This phase III, open-label, randomized (1:1) trial evaluated the immunogenicity, safety, and reactogenicity of adjuvanted RSVPreF3 when co-administered with RZV in ≥50-year-olds. The 2 vaccines were either co-administered at visit 1 (day [D] 1; Co-Ad), or were given sequentially, 1 month apart (RZV dose 1 at D1, adjuvanted RSVPreF3 at D31; Control). All participants received RZV dose-2 at D61. Non-inferiority of humoral immune responses was demonstrated if 95% confidence interval (CI) upper limits for geometric mean RSV-A/B neutralizing titers (GMT) and varicella-zoster virus anti-glycoprotein E (anti-gE) antibody concentration (GMC) ratios (Control/Co-Ad) were ≤1.5. Safety and reactogenicity were secondary endpoints. Results: Overall, 530 participants (Co-Ad = 265; Control = 265) were vaccinated. Neutralizing GMT ratios for RSV-A (1.1 [95% CI = 1.0–1.4]) and RSV-B (1.0 [0.8–1.2]), and anti-gE antibody GMC ratio (1.2 [1.1–1.4]) met non-inferiority criteria. Within 7 days post-vaccination, 71.7% (Co-Ad: post-RZV dose 1 and adjuvanted RSVPreF3; grade [Gr] 3 = 3.9%), 58.5% (Control: post-RZV dose 1; Gr3 = 1.9%), and 47.8% (Control: post-adjuvanted RSVPreF3; Gr3 = 1.2%) of participants reported solicited administration-site adverse events (AEs). Post-visit 1, 73.6% (Gr3 = 9.3%) of Co-Ad and 60.4% (Gr3 = 6.2%) of control participants reported solicited systemic AEs. Within 30 days post-any vaccination, 23.4% (Gr3 = 0.8%) of Co-Ad and 30.2% (Gr3 = 1.1%) of control participants reported unsolicited AEs. No fatal or related serious AEs were reported. Conclusions: Immunogenicity, reactogenicity, and safety data support the co-administration of adjuvanted RSVPreF3 and RZV. Clinical Trials Registration: NCT05966090.

Aims: This study investigated the real‐world clinical outcomes of switching from intermittently scanned continuous glucose monitoring (isCGM) to real‐time CGM (rtCGM) in adults with type 1 diabetes (T1D) from a large Canadian speciality care population.Methods: This retrospective observational study examined data from January 1, 2018, through July 31, 2023, in the Canadian LMC Diabetes Registry. The analysis measured 6–12‐month change in HbA1c in adults with T1D who switched from isCGM to rtCGM and compared changes to a propensity score‐matched isCGM cohort. Changes in number of hypoglycaemic events, CGM metrics, body weight, and total daily dose (TDD) of insulin were also evaluated at 6–12‐month follow‐up.Results: The full T1D rtCGM switch cohort comprised of 136 adults (mean: age 43 years, diabetes duration 20.9 years, baseline HbA1c 67 mmol/mol [8.2%]). For the full cohort, HbA1c was significantly lower at follow‐up compared to baseline (∆‐7 mmol/mol [∆‐0.6%], p < 0.001). The propensity score‐matched subset (n = 84) of these participants had a greater HbA1c reduction compared to the matched isCGM cohort (n = 84; adjusted mean difference, 5 mmol/mol [0.5%]; p = 0.002). The matched rtCGM switch subset had significantly higher time in range 3.9–10.0 mmol/L and lower time above range >10.0 mmol/L, time below range <3.9 mmol/L, and mean glucose compared to the isCGM cohort. There were no significant differences in hypoglycaemic events, body weight, and insulin TDD between the matched cohorts.Conclusions: This real‐world analysis of adults with T1D showed that switching from isCGM to rtCGM use led to significant improvements in HbA1c and CGM metrics.

Aims: We aimed to review the observational and randomised clinical trial evidence and provide pragmatic recommendations for using continuous glucose monitoring (CGM) in individuals living with noninsulin‐treated type 2 diabetes (T2DM). Materials and Methods: We first undertook a narrative review of observational studies that enrolled noninsulin‐users or mixed populations of noninsulin and insulin‐users with T2DM as well as randomised controlled trials (RCTs) that enrolled mixed populations with T2DM. We then performed a systematic review of the RCTs that specifically enrolled noninsulin‐treated populations with T2DM and compared CGM to BGM/usual care. A meta‐analysis of glycaemic outcomes was conducted with predefined subgroups based on CGM type. Results: RCTs in mixed populations and observational studies demonstrated a largely consistent benefit of CGM on glycaemic and nonglycaemic outcomes with cost effectiveness and reduced healthcare resource utilisation. The meta‐analysis of RCTs in noninsulin users included 8 studies encompassing 541 participants, among whom 297 (55%) were assigned to the CGM group. CGM was associated with significantly reduced HbA1c (weighted mean difference [WMD] −0.37%; 95% CI −0.49, −0.24; p < 0.00001; I ² = 0%), increased % time in range (WMD 8.84; 95% CI 4.62, 13.06; p < 0.0001; I ² = 0%) and lower % time above range (WMD −8.14; 95% CI −12.66, −3.63; p = 0.0004; I ² = 0%). There were no significant subgroup differences. Conclusions: CGM use in noninsulin‐treated individuals living with T2DM was associated with improved glycaemic outcomes and patient experience, reduced health care resource utilisation, and acceptable cost‐effectiveness. These findings provide additional evidence to support CGM use among people living with T2DM who are not using insulin therapy.

Background: The rising cost of insulins are significantly impacting health care expenditure, thereby limiting access to treatment for more people affected by diabetes. Fear and misunderstanding of insulin therapy have worsened with the emergence of biosimilar insulins. Biosimilars are not the same as generic medications. Generic medication contains identical ingredients to the reference, whereas biosimilar medication is highly comparable but not necessarily identical to the reference. Results: There are five biosimilar insulins currently available in Canada: insulin glargine (U‐100) as the biosimilar insulins, Basaglar® and Semglee®, insulin lispro (U‐100) as the biosimilar insulin, Admelog® and insulin aspart (U‐100) as the biosimilar insulins, Trurapi® and Kirsty ™. Recent clinical trials have demonstrated comparable efficacy, safety and immunogenicity for biosimilar insulins compared with reference insulins. The dosing of biosimilar insulins is also the same as the reference for initiating, switching (1:1) and titrating. Regulatory agencies, payors and clinical practice guideline committees are initiating biosimilar initiatives aimed at reducing costs, impacting more patients worldwide. While few studies have evaluated biosimilar insulin use in a real‐world clinical practice setting, the descriptive patterns retrieved from the LMC Diabetes Registry reflect the Ontario Ministry of Health's changes in biologic drug policy that were implemented to promote the use of biosimilar insulins. Conclusion: Many health care providers are largely unfamiliar with biosimilar insulins. This limits the acceptance of biosimilar insulins by patients, as it is related to the comfort of health care providers in educating patients. Tailoring effective conversations to patient needs ensures the best possible therapeutic outcomes. Plain Language Summary: This review article intends to review the efficacy and safety data from pivotal clinical trials with biosimilar insulins, as well as the regulatory and health economic considerations which underpin the safe and cost‐effective use of biosimilar insulin therapy. Biosimilars are not the same as generic medications. Generic medication contains identical ingredients to the reference, whereas biosimilar medication is highly comparable but not necessarily identical to the reference. There are five biosimilar insulins currently available in Canada: insulin glargine (U‐100) as the biosimilar insulins, Basaglar® and Semglee®, insulin lispro (U‐100) as the biosimilar insulin, Admelog® and insulin aspart (U‐100) as the biosimilar insulins, Trurapi® and Kirsty™. Data for biosimilars must be submitted in a stepwise approach to demonstrate similarity to the reference biologic under the following categories: structure & function, human clinical trials, comparative studies evaluating efficacy and safety and manufacturing quality control. Recent clinical trials have demonstrated comparable efficacy, safety and immunogenicity for biosimilar insulins compared with reference insulins. The dosing of biosimilar insulins is also the same as the reference for initiating, switching (1:1) and titrating. Health care providers are encouraged to stay up to date on the latest guidelines and recommendations regarding biosimilar insulin interchangeability to ensure safe and cost‐effective use of these products. Regulatory agencies, payors and clinical practice guideline committees are initiating biosimilar initiatives aimed at reducing costs, impacting more patients worldwide. While few studies have evaluated biosimilar insulin use in a real‐world clinical practice setting, the descriptive patterns retrieved from the LMC Diabetes Registry reflect the Ontario Ministry of Health's changes in biologic drug policy that were implemented to promote the use of biosimilar insulins. A summary of adults with diabetes from this registry showed 3.8% of individuals with T1D were prescribed Basaglar® before April 2023 compared to 12.0% after January 2024. For the T2D cohort, the use of basal biosimilar insulins, Basaglar® and Semglee®, similarly increased by approximately 10% and 2% after January 2024, respectively. The use of bolus biosimilar insulins also increased after January 2024 by approximately 28% in the T1D cohort and 60% in the T2D cohort using insulin therapy. Many health care providers are largely unfamiliar with biosimilar insulins. This limits the acceptance of biosimilar insulins by patients, as it is related to the comfort of health care providers in educating patients. People living with diabetes must have access to safe and effective treatment options, and they should be able to obtain appropriate medications at an affordable price and in a fair and timely manner.

Aim: To compare the effectiveness of adding a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) with adding basal insulin among adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) already treated with a sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i) and not reaching their glycaemic control targets. Methods: A retrospective analysis of the Canadian LMC Diabetes Registry was conducted. Adults who initiated a GLP‐1 RA were matched 1:1 to adults who initiated basal insulin in a T2D and CKD population. Changes in metabolic outcomes were evaluated at 26‐52 weeks following the therapy start date. Results: Propensity score matching was used to match participants who initiated a GLP‐1 RA to participants who initiated basal insulin ( n = 153/cohort). A significantly greater reduction in HbA1c at 26‐52 weeks of follow‐up was observed in the GLP‐1 RA cohort compared with the basal insulin cohort (−1.3% ± 1.4% vs. −1.1% ± 1.4%, P = .03). Weight was significantly reduced (−3.4 ± 3.7 vs. 2.6 ± 4.5 kg, P < .001), and the estimated glomerular filtration rate decline slowed significantly (−0.3 ± 8.2 vs. −2.4 ± 10.4 mL/min/1.73m ² , P = .02), but the change in albuminuria was not significantly different (−5.7 ± 38.1 vs. −0.5 ± 38.3 mg/mmol, P = .47) at follow‐up in the GLP‐1 RA group compared with the basal insulin group. No differences in self‐reported hypoglycaemic events per week and therapy discontinuations were reported between the cohorts. Conclusions: The study shows the real‐world effectiveness of GLP‐1 RA therapy for T2D and CKD. GLP‐1 RAs provided superior reductions in HbA1c and weight, and greater kidney protection, compared with basal insulin among adults with T2D and CKD already treated with an SGLT2i.

Real‐time continuous glucose monitoring (rtCGM) and intermittently scanned CGM (isCGM) have both been shown to improve glycaemic outcomes in people with T1D. The aim of this study was to compare real‐world glycaemic outcomes at 6–12 months in a propensity score matched cohort of CGM naïve adults with T1D who initiated a rtCGM or an isCGM. Among the matched rtCGM and isCGM cohorts (n = 143/cohort), rtCGM users had a significantly greater HbA_1c benefit compared to isCGM users (adjusted difference, −3 mmol/mol [95% CI, −5 to −1]; −0.3% [95% CI, −0.5 to −0.1]; p = 0.01). There was a significantly greater lowering of HbA_1c for rtCGM compared to isCGM when baseline HbA_1c was p < 0.001), and in MDI users (adjusted difference, −3 mmol/mol [95% CI, −6 mmol/mol to −0 mmol/mol]; −0.3% [95% CI ‐0.5% to 0.0%], p = 0.04). The rtCGM cohort had significantly greater time in range (58.3 ± 16.1% vs. 54.5 ± 17.1%, p = 0.03), lower time below range (2.1 ± 2.7% vs. 6.1 ± 5.0%, p < 0.001) and lower glycaemic variability compared to the isCGM cohort. In this real‐world analysis of adults with T1D, rtCGM users had a significantly greater reduction in HbA_1c at 6–12 months compared to isCGM, and significantly greater time in range, lower time below range and lower glycaemic variability, compared to a matched cohort of isCGM users.