Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin.

Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist ('twincretin')-a single molecule that acts as an agonist at both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. In the SURPASS clinical trial program in type 2 diabetes mellitus (T2D), tirzepatide was associated with unprecedented reductions in HbA1c, clinically significant weight loss and other metabolic benefits, combined with low rates of hypoglycaemia across a wide range of patient characteristics. The safety and adverse event rate for tirzepatide appears comparable to that of GLP-1 receptor agonists. Although results from dedicated cardiovascular (CV) and kidney trials are currently not available, information to date suggests that tirzepatide may have CV and kidney benefits in people with T2D. Tirzepatide has been approved for the treatment of T2D in the USA, United Arab Emirates, European Union, Japan and Australia. Here, we review how tirzepatide will fit into the T2D treatment continuum. We also consider future directions with tirzepatide in T2D, including its potential for targeting cardio-renal-metabolic disease in T2D, and discuss how tirzepatide-and other co-agonists in development-may challenge current approaches for management of T2D.

Early type 2 diabetes treatment intensification with glucagon-like peptide-1 receptor agonists in primary care: An Australian perspective on guidelines and the global evidence.

Early and intensive management of type 2 diabetes has been shown to delay disease progression, reduce the risk of cardiorenal complications and prolong time to treatment failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being increasingly recognized for their potential in early disease management, with recent guideline updates recommending second-line use of this injectable drug class alongside oral glucose-lowering drugs. GLP-1RAs target at least six of the eight core defects implicated in the pathogenesis of type 2 diabetes and offer significant glycaemic and weight-related improvements over other second-line agents in head-to-head trials. In addition, placebo-controlled clinical trials have shown cardiovascular protection with GLP-1RA use. Even so, this therapeutic class is underused in primary care, largely owing to clinical inertia and patient-related barriers to early intensification with GLP-1RAs. Fortunately, clinicians can overcome barriers to treatment acceptance through patient education and training, and management of treatment expectations. In this review we comment on global and Australian guideline updates and evidence in support of early intensification with this therapeutic class, and provide clinicians with practical advice for GLP-1RA use in primary care.

Effective primary care management of type 2 diabetes for indigenous populations: A systematic review.

BACKGROUND: Indigenous peoples in high income countries are disproportionately affected by Type 2 Diabetes. Socioeconomic disadvantages and inadequate access to appropriate healthcare are important contributors. OBJECTIVES: This systematic review investigates effective designs of primary care management of Type 2 Diabetes for Indigenous adults in Australia, Canada, New Zealand, and the United States. Primary outcome was change in mean glycated haemoglobin. Secondary outcomes were diabetes-related hospital admission rates, treatment compliance, and change in weight or Body Mass Index. METHODS: Included studies were critically appraised using Joanna Briggs Institute appraisal checklists. A mixed-method systematic review was undertaken. Quantitative findings were compared by narrative synthesis, meta-aggregation of qualitative factors was performed. RESULTS: Seven studies were included. Three reported statistically significant reductions in means HbA1c following their intervention. Seven components of effective interventions were identified. These were: a need to reduce health system barriers to facilitate access to primary care (which the other six components work towards), an essential role for Indigenous community consultation in intervention planning and implementation, a need for primary care programs to account for and adapt to changes with time in barriers to primary care posed by the health system and community members, the key role of community-based health workers, Indigenous empowerment to facilitate community and self-management, benefit of short-intensive programs, and benefit of group-based programs. CONCLUSIONS: This study synthesises a decade of data from communities with a high burden of Type 2 Diabetes and limited research regarding health system approaches to improve diabetes-related outcomes. Policymakers should consider applying the seven identified components of effective primary care interventions when designing primary care approaches to mitigate the impact of Type 2 Diabetes in Indigenous populations. More robust and culturally appropriate studies of Type 2 Diabetes management in Indigenous groups are needed. TRAIL REGISTRATION: Registered with PROSPERO (02/04/2021: CRD42021240098).

Sodium-glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review.

AIMS: To systematically review randomized controlled trials assessing effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on hospitalization for heart failure (HHF) and cardiac structure/function and explore randomized controlled trial (RCT)-derived evidence for SGLT2i efficacy mechanisms in heart failure (HF). METHODS AND RESULTS: Systematic searches of Medline and Embase were performed. In seven trials [3730-17 160 patients; low risk of bias (RoB)], SGLT2is significantly reduced the relative risk of HHF by 27-39% vs. placebo, including in two studies in patients with HF with reduced ejection fraction with or without type-2 diabetes mellitus (T2DM). Improvements in conventional cardiovascular risk factors, including glycaemic levels, cannot account for these effects. Five trials (56-105 patients; low RoB) assessed the effects of 6-12 months of SGLT2i treatment on left ventricular structure/function; four reported significant improvements vs. placebo, and one did not. Five trials (low RoB) assessed SGLT2i treatment effects on serum N-terminal pro B-type natriuretic peptide levels; significant reductions vs. placebo were reported after 8-12 months (two studies; 3730-4744 patients) but not ≤12 weeks (three studies; 80-263 patients). Limited available RCT-derived evidence suggests various possible cardioprotective SGLT2i mechanisms, including improved haemodynamics (natriuresis and reduced interstitial fluid without blood volume contraction/neurohormonal activation) and vascular function, enhanced erythropoiesis, reduced tissue sodium and epicardial fat/inflammation, decreased sympathetic tone, and beneficial changes in cellular energetics. CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors reduce HHF regardless of T2DM status, and reversal of adverse left ventricular remodelling likely contributes to this efficacy. Hypothesis-driven mechanistic trials remain sparse, although numerous trials are planned or ongoing.

Improving Type 2 Diabetes Management in General Practice Using a Second-Generation Basal Insulin Analogue Insulin Glargine 300 U/mL: A Practical Guide.

Type 2 diabetes management can be improved by the use of second-generation basal insulin analogues as the first choice on commencement of insulin, in this instance focussing on insulin glargine 300 U/mL (Gla-300). The clinical application of the use of Gla-300 include advantages such as less intra- and interpatient variability in glucose control resulting in rather less hypoglycaemia, longer duration of action and greater flexibility in the timing of administration thus suiting a wide range of patient presentations.Funding: Sanofi Australia.

Managing Cardiovascular Risk in Type 2 Diabetes: What Do the Cardiovascular Outcome Trials Mean for Australian Practice?

Understanding the implications of cardiovascular (CV) outcomes data of glucose-lowering agents on the management of type 2 diabetes mellitus can be challenging for many primary practitioners. Amongst different classes of diabetes medications assessed for CV safety, several agents within the sodium-glucose transport protein-2 inhibitor and glucagon-like peptide-1 receptor agonists classes have demonstrated CV risk reduction. Applying the trial findings to patients typically seen in clinical practice, such as those with established CV disease and those with multiple CV risk factors without established CV disease, requires further clarity. To bridge this gap in our current knowledge, the aim of this review was to utilise expert-driven opinions on common case scenarios and practical recommendations on the most appropriate choice of agents, according to an individual patient's clinical risk profile (CV and kidney disease), treatment preference and reimbursement environment from an Australian perspective.Funding: Boehringer Ingelheim Australia.

Benefits of simulated General Practice clinics in the preparation of medical students for primary healthcare.

The James Cook University (JCU) medical school has a mission to produce doctors who are willing to work across northern Australia and may choose generalist rather than specialist careers. In addition to real-life placements in primary healthcare settings, the medical school has developed simulated General Practice (GP) clinics (simGPclinic) for Year 5 (Y5) students. This study compares the simGPclinic with actual GP placements for authenticity, teaching clinical skills, and preparation for real-life primary healthcare settings. Y5 students were administered a survey following their simGPclinic (n = 65; response rate = 97%). Students rated the simGPclinic's authenticity as 77 out of 100, and were more likely to rate the simGPclinic as being 'better' than their real-life GP placement in teaching them to: 'formulate a medical management plan and order correct pathology tests'; 'rule out the "red flags" for the key clinical problem'; 'undertake a patient-centred history and examination'; 'make a differential diagnosis for the key clinical problem'; and, 'develop communications skills'. The simGPclinic provided medical students with authentic and positive learning experiences in primary healthcare that were at least as beneficial as those provided in real-life settings, as well as being more reliable and better structured.

GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective.

The ever-increasing number of drugs available to treat type 2 diabetes and the complexity of patients with this condition present a constant challenge when it comes to identifying the most appropriate treatment approach. The more recent glucagon-like peptide-1 receptor agonists (GLP-1RAs) are non-insulin injectable options for the management of type 2 diabetes. Effective at improving glycaemic control with a low intrinsic risk of hypoglycaemia and the potential for weight reduction, this agent class is an important addition to the prescribing armamentarium. However, understanding their place in therapy may prove confusing for many primary care practitioners, especially given the common belief that 'injectables' are a last-resort treatment option, which puts them at risk of being niched alongside insulin. This review summarises the clinical evidence for GLP-1RAs and how they compare to other glucose-lowering agents in managing type 2 diabetes. It also provides practical and case-driven opinions and recommendations on the optimal use of GLP-1RAs by discussing important patient factors and clinical considerations that will help to identify those who are most likely to benefit from this class of agents.Funding: Eli Lilly Australia.

Growth of the James Cook University Medical Program: Maintaining quality, continuing the vision, developing postgraduate pathways.

BACKGROUND: James Cook University (JCU) enrolled its first cohort of 64 in 2000 into a 6-year undergraduate medical program aimed at producing graduates capable of meeting the needs of North Queensland, Australia, with a focus on rural, remote, Indigenous and tropical health. The school's 1465 graduates over 13 cohorts who have a pattern of practice likely to meet the region's health needs. The JCU course was the first new Australian medical program for 25 years. The number of Australian medical schools has since doubled, while enrollments have almost tripled. METHODS: JCU's course features innovations such as dispersed, community-based education, rurally-focused selection, extended rural placements, and an emphasis on community needs - which are all now mainstream. This paper traces developments at JCU over the past decade, illustrating parallels with the broader Australian scene. RESULTS: Maintaining quality and educational integrity while numbers grow is challenging. The course has undergone modest curriculum redesign, but the fundamental elements are intact. The focus on meeting the region's needs remains, with some evolution of its mission to include social accountability and the needs of underserved populations. CONCLUSIONS: Postgraduate pathways are an important priority. Regional training hubs are being developed to support local pipelines into specialty practice. Queensland's Rural Generalist Pathway provides an incentivised pathway to rural practice while Generalist Medical Training provides a local training pipeline into general practice and rural medicine. As these initiatives mature, communities should benefit as JCU and other Australian programs continue to address local workforce needs.

The road to registration: Aboriginal and Torres Strait Islander health practitioner training in north Queensland.

CONTEXT: In 2012, the new profession of Aboriginal and Torres Strait Islander health practitioner (ATSIHP) was registered under the Health Practitioner Regulation National Law Act 2009. The project in this present study evolved out of the Australian Government\'s recognition of the need for the existing Indigenous health worker (IHW) workforce to meet the minimum qualification requirements for registration as ATSIHPs through recognition of prior learning and/or further education. A total of 53 IHWs participated in the upskilling project between June 2014 and June 2015, with approximately 200 IHWs from Queensland expressing an interest in undertaking the training. This demonstrated a clear need for further training programs such as this one. The project was coordinated by the Indigenous Health Unit at James Cook University (JCU) with training being delivered by TAFE Cairns in collaboration with the College of Medicine and Dentistry, JCU. Students travelled from as far north as the Torres Strait and as far west as Mount Isa. ISSUES: The key issues for discussion were associated with the ATSIHP role being relatively new including the limited preparedness of training providers to deliver the upgraded qualification requirements and uncertainty about the registration process. Compounding this was a general undervaluing and underutilisation of the IHW role within the current primary healthcare system. Other challenges included the variations of IHW roles, scope of practice and educational standards held by individuals, as well as the associated complexities of providing training to IHWs from the large and diverse geographic area that is rural and remote Australia. Program and student evaluation was undertaken with each of the three cohorts via a course experience questionnaire, TAFE evaluation forms and opportunistic student feedback. LESSONS LEARNED: Lessons learned as a result of this project include the need to continue to recognise and promote understanding of the contribution that IHW/ATSIHPs make in improving health, the importance of conducting a comprehensive student selection process, the benefits of working collaboratively between the university and vocational education training sectors, the need to continue to strengthen partnerships between higher education and health industry, the need for flexible funding and training models that enable adequate learning support, and the identification of a significant unmet training need.

Medication calculation and administration workshop and hurdle assessment increases student awareness towards the importance of safe practices to decrease medication errors in the future.

BACKGROUND: Medication errors are the second most frequently reported hospital incident in Australia and are a global concern. A "Medication Calculation and Administration" workshop followed by a "hurdle" assessment (compulsory task mandating a minimum level of performance as a condition of passing the course) was introduced into Year 2 of the James Cook University medical curriculum to decrease dosage calculation and administration errors among graduates. This study evaluates the effectiveness of this educational activity as a long-term strategy to teach medical students' essential skills in calculating and administering medications. METHODS: This longitudinal study used a pre- and post-test design to determine whether medical students retained their calculation and administration skills over a period of 4 years. The ability to apply basic mathematical skills to medication dose calculation, principles of safe administration (Part 1), and ability to access reference materials to check indications, contraindications, and writing the medication order with correct abbreviations (Part 2) were compared between Year 2 and 6 assessments. RESULTS: Scores for Parts 1, 2 and total scores were nearly identical from Year 2 to Year 6 (P = 0.663, 0.408, and 0.472, respectively), indicating minimal loss of knowledge by students in this period. Most Year 6 students (86%) were able to recall at least 5 of the "6 Rights of Medication Administration" while 84% reported accessing reference material and 91% reported checking their medical calculations. DISCUSSION: The "Medication Calculation and Administration" workshop with a combined formative and summative assessment - a "hurdle" - promotes long-term retention of essential clinical skills for medical students. These skills and an awareness of the problem are strategies to assist medical graduates in preventing future medication-related adverse events.

Short-chain fatty acids increase expression and secretion of stromal cell-derived factor-1 in mouse and human pre-adipocytes.

OBJECTIVE: Stromal cell-derived factor-1 (SDF-1) is expressed in pre-adipocytes but its role is unknown. We investigated butyrate (a histone deacetylase inhibitor--HDACi) and other short-chain fatty acids (SCFA) in the regulation of SDF-1. We further investigated whether effects of SCFA were signalled through G protein-coupled receptors FFA2 and FFA3. DESIGN AND RESULTS: SDF-1 mRNA expression and protein secretion were studied in 3T3-L1 cells and human pre-adipocytes. SDF-1 was abundant, with mRNA and protein levels increased by butyrate. This was replicated with acetate and propionate, but not with trichostatin or valproate. Trichostatin inhibited SDF-1 secretion. Pertussis toxin blocked stimulation by butyrate. The order of potency of SCFA in stimulating SDF-1 (C3 > C4 > C2) is consistent with action through FFA3. Silencing the FFA3 gene abolished butyrate-stimulated SDF-1 expression and secretion. FFA3 was expressed in both pre-adipocytes and adipocytes, while FFA2 was expressed in adipocytes only. SDF-1 expression was low in murine macrophage J774.2 cells, while the SDF-1 receptor CXCR4 was absent from 3T3-L1 cells but abundant in J774.2 macrophages. In human pre-adipocytes, FFA3 was also expressed and SCFA increased SDF-1 secretion. CONCLUSIONS: SDF-1 and CXCR4 may mediate the interaction between adipose stromal cells and macrophages. Effects of SCFA are mediated through FFA3, but not histone deacetylase inhibition.

Hydroxyoctadecadienoic acids regulate apoptosis in human THP-1 cells in a PPARγ-dependent manner.

Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP-1 monocytes and adherent THP-1 cells were compared with other C18 fatty acids, LA and α-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p < 0.01, 30 µM) and 13 HODE (p < 0.01, 30 µM), and the equivalent cell viability was also decreased (p < 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p < 0.001) in both monocytes and adherent THP-1 cells, with 9-HODE the more potent. In addition, 9-HODE and 13-HODE both increased Annexin-V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1 µM), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10 µM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ-regulated apoptotic effects induced by 9-HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9-HODE and 13-HODE are potent--and specific--regulators of apoptosis in THP-1 cells. Their action is PPARγ-dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis.