Stephen C. Bain

Type 1 diabetes (T1D), type 2 diabetes (T2D) and Alzheimer’s disease (AD), which are heterogeneous multifactorial diseases, have become major global healthcare burdens and significant concerns for the future. Historically, the pathogeneses of these diseases were regarded as being largely distinct, but recent research suggests that this view is now outdated, with a lack of insulin and/or insulin resistance playing an important role in both forms of diabetes and AD. The current state of knowledge on the epidemiology, aetiology, and pathogenesis of T1D, T2D, and AD is summarised in this review. The evidence demonstrating overlapping pathological features between these diseases is also discussed here. Studies have demonstrated that islet autoimmunity, dysfunctional glucagon secretion, insulin resistance and islet amyloidosis manifest in both T1D and T2D. AD has been suggested to be type 3 diabetes (T3D), due to the associated abnormal brain insulin resistance, which is speculated to drive the progressive pathogenesis. Additionally, T1D and T2D are risk factors for AD and vice versa, and most AD patients also have diabetes or glucose intolerance, indicating bidirectional relationships. Thus, the association between AD and diabetes is already well established. Further understanding the connection between these diseases using recent scientific evidence may allow for the development of more efficient therapeutic strategies, which is highly desirable, given the prevalence of post-diagnosis complications. Evidence suggests that GLP-1R agonists can alleviate the phenotypes of all of these diseases, and these agonists could be used in the future to simultaneously treat them in subjects or prevent/delay their manifestation in at-risk individuals.

Corrigendum for the article A Review of Current Trends with Type 2 Diabetes Epidemiology, Aetiology, Pathogenesis, Treatments and Future Perspectives

Objectives: This study investigated the relationship between interstitial and blood glucose concentrations following ingestion of carbohydrate-containing drinks differing in carbohydrate amount, osmolarity, and glycaemic index. Methods: Ten healthy adults (nine male; age: 22 ± 1 y; height: 177 ± 12 cm; weight: 75 ± 14 kg) completed a double-blind, randomised cross-over study with seven beverage trials varying in carbohydrate (CHO) characteristics. Blood samples were collected at rest and over two hours, while interstitial glucose ([iG]) was recorded using a continuous glucose monitor (Supersapiens, Atlanta, USA). Glycaemic metrics and mean absolute relative difference (MARD) were calculated for hypoglycaemic, euglycaemic, and hyperglycaemic ranges. Data were analysed using repeated-measures ANOVA with Bonferroni correction and paired t-tests (p ≤ 0.05). Results: Interstitial and blood glucose concentrations were similar at baseline but diverged post-ingestion. MARD varied by glucose rate and direction, exceeding 20% during rapid declines (>2 mg/dL/min), where [iG] underestimated [BG] by −7.3 ± 27.1 mg/dL. Accuracy was highest during stable glucose (MARD = 10.5 ± 8.6%). Carbohydrate amount and glycaemic index influenced peak glucose, whereas beverage concentration (5–20%) had minimal effect when CHO amount was fixed, though variation in CGM agreement appeared during post-peak declines. Conclusions: CGM tracked blood glucose overall but showed reduced accuracy during rapid falls or hypoglycaemia. Carbohydrate properties influenced glycaemic response but not sensor agreement when CHO load was constant. Glucose rate and direction of change are key considerations for interpreting CGM data in research and applied settings.

Aims: To compare the effects of dose reductions of ultra‐rapid‐acting insulin aspart (URA‐IAsp) and rapid‐acting insulin aspart (IAsp) on blood glucose concentrations during continuous moderate‐intensity exercise in people with type 1 diabetes (T1D). Materials and Methods: In this double‐blind, laboratory‐controlled study, 43 adults with T1D completed four experimental visits in a randomised crossover design. Participants injected a 50% or 75% reduced dose of URA‐IAsp or IAsp with a standardised breakfast 60 min prior to 45 min of cycling at ~61% V̇O _2peak . The same insulin type and dose were administered 4 h after the first injection, alongside an identical lunch meal. Venous blood samples were taken at 5‐, 10‐, and 15‐min epochs, for a total of 70 timepoints, throughout the trial day until 4 h after the second injection to determine blood glucose and insulin concentrations. The primary endpoint was the four‐way comparison of blood glucose change from exercise start to end. Results: Blood glucose declined during exercise to a similar extent between 50% dose URA‐IAsp (−4.0 ± 2.8 mmol L ⁻¹ ) and all other conditions (all p > 0.05), yet fell more in the 50% IAsp dose (−5.1 ± 3.0 mmol L ⁻¹ ) compared to the URA‐IAsp (−2.8 ± 3.3 mmol L ⁻¹ ) and IAsp (−3.4 ± 3.3 mmol L ⁻¹ ) 75% reduced dose conditions (both p < 0.05). Differences in blood insulin concentrations between trials were only resultant of insulin doses and not insulin type from 30 min after the first insulin injection. Conclusions: Insulin dose reductions around acute moderate‐intensity exercise yield similar glucose‐lowering effects with URA‐IAsp and IAsp. The extent of dose reductions exerts greater influence on glycaemia than the type of fast‐acting insulin.

Aims: There is current apprehension among some clinicians and conflicting evidence regarding ocular complications in relation to Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). We aimed to generate multi‐disciplinary, expert‐led consensus recommendations relating to ocular complications to facilitate optimum prescribing of GLP‐1RAs. Materials and Methods: A modified Delphi was conducted following the ACcurate COnsensus Reporting Document (ACCORD) for Delphi research. A structured literature review informed an anonymous online Delphi questionnaire, followed by a virtual consensus meeting. Eligible participants included ophthalmologists, diabetologists, and obesity specialists practising in Europe. Results: Responses from 58 participants across 17 countries were analysed. Respondents agreed that diabetic retinopathy (DR) worsening events are primarily linked to rapid blood glucose‐lowering, rather than a direct drug effect. The benefits of GLP‐1RAs were deemed to outweigh potential ocular risks and should not limit access to these medicines. Prescribers should ensure that people with diabetes are screened for diabetic retinopathy before commencing GLP‐1RAs, particularly in high‐risk populations (>10 years duration and/or poor glucose control, (haemoglobin A1c [HbA1c] >10% or 86 mmol/mol)). When prescribing GLP‐1RA to those with sight loss in one eye and/or prior history of non‐arteritic anterior ischaemic optic neuropathy (NAION), the risk of ocular complications should be discussed. The Delphi study highlighted current uncertainty in the evidence, with some topics on the relationship between GLP‐1RAs and ocular complications reaching limited consensus. Conclusions: Further research is needed into the direct effects of GLP‐1RAs on the retina and ocular complications. New evidence should be disseminated rapidly to optimise outcomes and safety.

BACKGROUND: Both GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter-2) inhibitors (SGLT2i) improve cardiovascular outcomes in people with type 2 diabetes and cardiovascular or chronic kidney disease. However, there are limited data about the effect of combining these agents on cardiovascular and safety outcomes. METHODS: The SOUL trial (Semaglutide Cardiovascular Outcomes Trial; NCT03914326) randomized 9650 participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease to oral semaglutide or placebo. As prespecified, participants were analyzed according to baseline use of SGLT2i (yes, n=2596; no, n=7054), and subsequently for any use of SGLT2i during the trial (yes, n=4718; no, n=4932). The primary outcome was time to first major adverse cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Safety was evaluated by comparing the incidence of serious adverse events. RESULTS: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide versus placebo (hazard ratio, 0.86; 95% CI, 0.77–0.96). In those taking SGLT2i at baseline, there were 143 of 1296 (semaglutide) versus 158 of 1300 (placebo) primary outcome events (hazard ratio, 0.89; 95% CI, 0.71–1.11); and 436 of 3529 versus 510 of 3525, respectively, in participants not taking SGLT2i at baseline (hazard ratio, 0.84; 95% CI, 0.74–0.95; P -interaction, 0.66). An analysis of major adverse cardiovascular events by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar. CONCLUSIONS: Oral semaglutide reduced major adverse cardiovascular event outcomes independently of concomitant SGLT2i treatment, and this combination appeared to be safe. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03914326.

Introduction The ONWARDS programme assessed the efficacy and safety of once-weekly insulin icodec (icodec) versus once-daily basal insulin comparators in type 2 diabetes (T2D) or type 1 diabetes (T1D). This post hoc exploratory analysis of ONWARDS 1–6 assessed the impact of icodec during and around hospitalisation. Methods ONWARDS 1–6 were randomised, two-arm, phase 3a trials (ClinicalTrials.gov: NCT04460885; NCT04770532; NCT04795531; NCT04880850; NCT04760626; NCT04848480). Adults with T2D (ONWARDS 1–5; n = 3765) and T1D (ONWARDS 6; n = 582) received icodec or once-daily comparators (insulin degludec, insulin glargine U100, insulin glargine U300). Hospitalised cases were analysed for: hospitalisation duration, icodec dose, self-measured blood glucose, glycated haemoglobin (HbA_1c) levels, and clinically significant and severe hypoglycaemia before, during, and after hospitalisation. Results Across trials, a similar number of participants receiving icodec (n = 152/2172) and once-daily comparators (n = 156/2175) were hospitalised. Median duration of hospital stay was similar between treatment groups (icodec, 5.0 days; once-daily comparators, 6.0 days); icodec dose remained fairly stable around hospitalisation. Most hospitalised participants completed the trial without permanently discontinuing treatment (icodec, 84.9%; once-daily comparators, 90.4%). Mean HbA_1c levels remained relatively stable over assessed time points for both treatment groups. Six participants receiving icodec (one with T2D; five with T1D) and three receiving once-daily comparators (one with T2D; two with T1D) reported clinically significant or severe hypoglycaemia during hospitalisation. Conclusions Similar numbers of hospitalisations were reported in both treatment arms. Icodec treatment was continued during hospitalisation in most participants and did not appear to have an impact on glycaemic management or hypoglycaemia. This analysis suggests that once-weekly icodec could be managed in a similar way to once-daily basal insulin analogues during hospitalisation. Trial Registration ClinicalTrials.gov identifiers, NCT04460885 (ONWARDS 1), NCT04770532 (ONWARDS 2), NCT04795531 (ONWARDS 3), NCT04880850 (ONWARDS 4), NCT04760626 (ONWARDS 5), NCT04848480 (ONWARDS 6).

Introduction Clinical trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes (T2D) who have established cardiovascular disease (CVD) or a high risk of CVD. Nevertheless, GLP-1RAs remain underutilized. This real-world, retrospective study compared cardiovascular and economic outcomes between individuals treated with GLP-1RAs and other glucose-lowering agents in England. Methods Clinical Practice Research Datalink-registered people indexed on GLP-1RAs, dipeptidyl peptidase-4 (DPP4) inhibitors, or basal insulin between January 1, 2014 and December 31, 2018 for their fourth line of T2D treatment were stratified into six cohorts based on their: (1) cardiovascular risk (high or very high risk) and (2) indexed therapy. Cox proportional hazards regression was used to compare the risk of MACE and all-cause death between GLP-1RA and other treatment cohorts. Generalized linear regression was used to quantify differences in healthcare resource use (HCRU) and costs between groups. Results Of 63,237 subjects, 10,607 were at high cardiovascular risk (GLP-1RA: 2709; DPP4 inhibitor: 2673; basal insulin: 5225) and 52,630 at very high cardiovascular risk (GLP-1RA: 14,692; DPP4 inhibitor: 18,461; basal insulin: 19,477). The crude incidence of all outcomes was lower in the GLP-1RA versus other treatment cohorts, regardless of cardiovascular risk. Among very-high-risk individuals treated with GLP-1RA, the adjusted risk of MACE was 33% (24–40%) and 23% (13–23%) lower versus DPP4 inhibitor and basal insulin cohorts, respectively. The adjusted total cardiovascular-related cost among very-high-risk individuals was £208.14 (£155.81–£260.47) and £151.74 (£110.69–£192.79) lower in the GLP-1RA versus DPP4 inhibitor or basal insulin cohorts, respectively. Conclusions In a real-world setting, GLP-1RAs may be associated with a lower risk of MACE and reduced HCRU and costs than DPP4 inhibitors or basal insulin in individuals with T2D, particularly among those at very high cardiovascular risk.

Introduction The high risk of cardiovascular events in people with type 2 diabetes increases with age. The cardiovascular effects of once-weekly subcutaneous and once-daily oral semaglutide versus placebo in people with type 2 diabetes at high cardiovascular risk were investigated in the SUSTAIN 6 and PIONEER 6 cardiovascular outcomes trials, respectively. It is unknown whether the effects of semaglutide are age dependent. Methods This post hoc analysis evaluated cardiovascular, metabolic, and safety outcomes with semaglutide versus placebo in age subgroups (≤ 60; > 60 to ≤ 65; > 65 to ≤ 70; and > 70 years) pooled from SUSTAIN 6 and PIONEER 6. Major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), changes from baseline in glycated hemoglobin A_1c (HbA_1c) and body weight, and adverse events were analyzed. Results Semaglutide reduced major adverse cardiovascular events and its components versus placebo across age subgroups (most hazard ratios < 1.0; p_interaction > 0.05). The treatment difference in HbA_1c reduction was greater in those aged ≤ 60 years than in older subgroups (p_interaction = 0.01). Reductions in body weight with semaglutide versus placebo were consistent across age subgroups (p_interaction = 0.124). Serious adverse events or severe hypoglycemic episodes did not differ between semaglutide and placebo across age subgroups. Conclusion Semaglutide consistently reduced major adverse cardiovascular events and body weight versus placebo across age subgroups; its safety profile did not differ with age. These results suggest that relaxing HbA_1c targets based solely on age may not always be required for people with type 2 diabetes. Trial Registration SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) are registered at ClinicalTrials.gov.