February 2025

Abstract
Aims
To evaluate early glycaemic control (glycated haemoglobin [HbA1c] < 7.0% [<53.0 mmol/mol], fasting plasma glucose [FPG] ≤ 7.0 mmol/L or postprandial glucose [PPG] ≤ 10.0 mmol/L) with iGlarLixi versus insulin glargine 100 U/mL (Gla-100) in Asian people with suboptimally controlled type 2 diabetes (T2D) on oral antidiabetic drugs (OADs) in LixiLan-O-AP or basal insulin (BI) ± OADs in LixiLan-L-CN.
Materials and Methods
This post hoc analysis evaluated changes from baseline to Week 12 in HbA1c, FPG and PPG, hypoglycaemia incidence and the rates of target HbA1c achievement at Weeks 8 and 12. Median time to glycaemic control (i.e., time to 50% achieving target HbA1c, FPG or PPG) was also assessed.
Results
At Week 12, mean HbA1c reductions were greater with iGlarLixi versus Gla-100 in LixiLan-O-AP (−1.6% vs. −1.1% [−17.0 vs. −12.0 mmol/mol]) and LixiLan-L-CN (−1.3% vs. −0.5% [−13.9 vs. −5.4 mmol/mol]). PPG reductions were greater with iGlarLixi, while FPG reductions and hypoglycaemia incidence were similar. At Weeks 8 and 12, more participants had achieved target HbA1c or PPG with iGlarLixi versus Gla-100 in both studies. Median time to achieve HbA1c and PPG targets was shorter with iGlarLixi versus Gla-100 in LixiLan-O-AP (85 vs. 126 days and 84 vs. 167 days) and LixiLan-L-CN (85 vs. 239 days and 85 days vs. not estimable); median time to achieve FPG target was similar in LixiLan-O-AP (57 vs. 57 days) and LixiLan-L-CN (29 vs. 30 days).
Conclusions
In Asian people with T2D suboptimally controlled on OADs or BI, iGlarLixi provided comprehensive earlier glycaemic control than Gla-100.

Abstract
Aims
Individuals with liver insulin-resistant (LIR) or muscle insulin-resistant (MIR) phenotypes may respond differently to dietary interventions. Given the interaction between insulin resistance and cardiovascular risk, this sub-analysis of the PERSON study examined whether a personalized diet according to MIR or LIR phenotypes improves vascular function and cardiovascular disease risk factors.
Materials and Methods
We randomized 119 participants to a 12-week low-fat, high-protein, high-fibre diet (LFHP; may be optimal for LIR) or Mediterranean diet (high in monounsaturated fat, HMUFA; may be optimal for MIR). Randomization linked the insulin-resistant (IR) phenotype to the proposed optimal diet, leading to PhenoDiet A (MIR-HMUFA and LIR-LFHP) and PhenoDiet B (MIR-LFHP and LIR-HMUFA). Before and after the intervention, vascular function (carotid artery reactivity) and cardiovascular risk factors (blood pressure, total cholesterol, HDL-cholesterol and Framingham risk score) were examined. A 7-point oral glucose tolerance test was performed to determine insulin resistance (Matsuda index and HOMA-IR) and disposition index.
Results
Following drop-out (n = 18), 101 participants finished the intervention (54 women, 61 ± 7 years, 27.6 [26.4;30.0] kg/m2), with n = 80 available for the primary outcome of vascular function. Overall, the dietary interventions significantly decreased blood pressure, total cholesterol, HDL-cholesterol and the Framingham risk score (all p < 0.05), while vascular function was not affected (p = 0.485). Insulin resistance (p ≤ 0.001), but not disposition index (p = 0.362), was significantly improved after intervention. The Matsuda index (p = 0.078) tended to increase more and total cholesterol (p = 0.052) tended to decrease more in PhenoDiet group B than A, but other changes in outcome parameters were not significantly different between PhenoDiet groups. The LFHP diet resulted in more pronounced improvements in cholesterol, diastolic blood pressure (DBP) and insulin resistance compared with the HMUFA diet (all p < 0.05).
Conclusion
A 12-week diet improves metabolic and cardiovascular outcomes, but not vascular function in insulin-resistant adults with overweight or obesity. Whilst the LFHP diet resulted in greater improvements in cardiometabolic risk markers than the HMUFA diet, we found no significant differences between the PhenoDiet groups.

Abstract
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.

Diabetes, Obesity and Metabolism, EarlyView.

Abstract
Aims
This study investigated the role of plasma proteins in obesity to identify predictive biomarkers and explore underlying biological mechanisms.
Methods
In the Cooperative Health Research in the Region of Augsburg (KORA) FF4 study, 809 proteins were measured in 2045 individuals (564 obese and 1481 non-obese). Multivariate logistic regression adjusted for confounders (basic and full models) was used to identify obesity-associated proteins. Priority-Lasso was applied for feature selection, followed by machine learning models (support vector machine [SVM], random forest [RF], k-nearest neighbour [KNN] and adaptive boosting [Adaboost]) for prediction. Correlation and enrichment analyses were performed to elucidate relationships between protein biomarkers, obesity risk factors and perturbed pathways. Mendelian randomisation (MR) assessed causal links between proteins and obesity.
Results
A total of 16 proteins were identified as significantly associated with obesity through multivariable logistic regression in the basic model and subsequent Priority-Lasso analysis. Enrichment analyses highlighted immune response, lipid metabolism and inflammation regulation were linked to obesity. Machine learning models demonstrated robust predictive performance with area under the curves (AUC) of 0.820 (SVM), 0.805 (RF), 0.791 (KNN) and 0.819 (Adaboost). All 16 proteins correlated with obesity-related risk factors such as blood pressure and lipid levels. MR analysis identified AFM, CRP and CFH as causal and potentially modifiable proteins.
Conclusions
The protein signatures identified in our study showed promising predictive potential for obesity. These findings warrant further investigation to evaluate their clinical applicability, offering insights into obesity prevention and treatment strategies.

Purpose of review

The aim of this review is to examine recent advancements in RNA-targeted therapies for the management of severe hypertriglyceridemia (sHTG) and prevention of sHTG-associated acute pancreatitis.

Recent findings

Recent developments in RNA-targeted therapies, aimed at inhibiting apolipoprotein C-III (apoC-III), have demonstrated substantial and sustained reductions in triglyceride levels. Novel therapies, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), such as volanesorsen, olezarsen, and plozasiran, have shown promising results in recent trials. These therapies not only effectively lower plasma triglyceride levels but also significantly reduce the incidence of acute pancreatitis.

Summary

SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention.

Professor Christina Vogel (The Center for Food Policy, City St George’s) and Dr. Preeti Dhuria (University of Southampton) discuss how weak enforcement lets retailers bypass UK obesity regulations.

Abstract
Aims
Obesity and its complications contribute to the burden of cardiovascular disease (CVD). Here, we characterised individuals with high body mass index (BMI) and established CVD by assessing healthcare resource utilisation (HCRU) and costs, incidence of cardiovascular (CV) events and mortality.
Materials and Methods
This was a retrospective open cohort study using UK Discover data (study period: January 2004 to December 2019). Included were individuals aged ≥45 years with BMI ≥ 27 kg/m2, without type 1 or type 2 diabetes, and with established CVD (previous myocardial infarction, stroke or peripheral artery disease). Serial annual cross sections were assembled to generate prevalence and incidence cohorts and for mapping of HCRU, costs and the incidence of selected events. CVD and mortality trajectories were modelled using a Markov model. HCRU and costs were layered onto this model to obtain associated trajectories.
Results
In 2019, annual per-person healthcare costs for individuals with high BMI and established CVD (n = 27 313) were £3364. During 2015–2019, the incidence of major adverse CV events was 2812 per 100,000 person-years; the incidences of all-cause and CV mortality were 2896 and 774 per 100,000 person-years, respectively. Over 2022–2031, this population is projected to accrue estimated healthcare costs of £40.8 million. HCRU trajectory drivers included a history of CV events, older age, and multimorbidity.
Conclusions
Owing to a high disease and treatment burden, people with a history of CVD living with high BMI incur substantial healthcare costs and are at risk of mortality.