Acute Interstitial Nephritis and Oxalate Nephropathy After Rapid Pasireotide Response in Treatment-resistant Acromegaly.

We report a case of interstitial nephritis, likely secondary to oxalate nephropathy, due to the development of pancreatic exocrine dysfunction after commencement of pasireotide for acromegaly. Pasireotide is known to impair insulin secretion but can also impair pancreatic exocrine function, hypothezised to result from high-affinity binding of somatostatin receptors 1, 2, 3, and 5. This has been an advantage in postoperative tissue anastomoses after pancreatic surgery, but exocrine insufficiency has not been reported when used for the treatment of acromegaly. A 73-year-old woman, diagnosed with acromegaly, was unable to achieve biochemical control despite 2 surgical resections of an invasive mammosomatotroph pituitary tumor and treatment with cabergoline and maximal-dose lanreotide. The tumor expressed somatostatin receptor type 5 but not somatostatin receptor type 2, predicting good response from pasireotide, which was commenced at 40 mg every 4 weeks. IGF-1 rapidly normalized, but the patient presented with nausea, anorexia, and acute kidney injury. Renal biopsy revealed acute-on-chronic interstitial nephritis, with numerous oxalate crystals. Increased fecal fat globules were noted on fat stain (3+), supporting malabsorption as an etiology of secondary enteric hyperoxaluria. Renal function recovered to near baseline over months following pasireotide withdrawal and high-dose glucocorticoids.

Geographic variation in sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.

Classification of type 1 diabetes: A pathogenic and treatment-based classification.

AIM: To improve the diagnosis and classification of patients who fail to satisfy current type 1 diabetes diagnostic criteria. METHODS: Review of the literature and current diagnostic guidelines. DISCUSSION: We propose a novel, clinically useful classification based on islet autoantibody status and non-fasting C-peptide levels. Notably, we discuss the subgroup of latent autoimmune diabetes in the young and propose a new subgroup classification of autoantibody negative type 1 diabetes in remission. CONCLUSION: A novel classification system is proposed. Further work is needed to accurately diagnose and manage minority type 1 diabetes subgroups.

'We are somehow fixated on this being a diabetes drug': a qualitative study exploring the views of cardiologists and nephrologists about sodium-glucose cotransporter 2 inhibitor initiation.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs. AIMS: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i. METHODS: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis. RESULTS: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes. CONCLUSIONS: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation.

Prescribing patterns of adjunctive therapy for the treatment of type 1 diabetes mellitus among Australian endocrinologists.

BACKGROUND: Many people living with type 1 diabetes (type 1 diabetes mellitus (T1DM)) do not meet glycaemic targets. Adjunctive therapies have both risks and metabolic benefits and may have a role in selected patients. AIM: To review the prescribing patterns of adjunctive therapy for the treatment of T1DM diabetes in Australia. METHODS: We conducted an online survey of Australian endocrinologists and endocrinology registrars. We surveyed the frequency of, motivations and concerns regarding the prescription of metformin, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose transport protein 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonist (GLP1RA) in T1DM. RESULTS: Fifty-two practitioners participated. Most respondents (94%) had prescribed adjuncts for the treatment of T1DM in some form. Weight (89%), large insulin doses (73%), glycaemic variability (52%), high HbA1c (48%) and the presence of cardiovascular disease (48%) were the most common factors determining the use of adjuncts. The most commonly prescribed adjuncts were metformin (94%) and SGLT-2 inhibitors (65%). Respondents who had never prescribed an SGLT-2 inhibitor (n = 18) reported risk of diabetic ketoacidosis (DKA) (100%), off-label status (39%), lack of evidence (39%), withdrawal of support from the European Medicines Agency (17%) and cost (17%) as factors contributing to their decision. Thirty-one respondents (60%) had prescribed a GLP1RA. Among those who had never prescribed a GLP1RA (n = 21), off-label status (57%), lack of evidence (48%), cost (38%) and expected lack of efficacy (14%) were factors affecting their decision. Only five respondents (10%) had prescribed a DPP-IV inhibitor. CONCLUSION: Australian endocrinologists commonly prescribe adjuncts to address cardiometabolic concerns in T1DM. DKA risk and off-label status are significant factors contributing to reluctance to prescribe.

Glucagon-like Peptide-1 Receptor Agonist Treatment With Semaglutide in Type 1 Diabetes.

The efficacy of glucagon-like peptide-1 receptor agonists in type 2 diabetes is well established, but their role in type 1 diabetes (T1DM) is less clear. A 36-year-old woman with a 27-year history of T1DM and undetectable c-peptide presented for review of weight management, with body mass index 29.3 kg/m2. A previous trial of dapagliflozin led to no improvement in weight or glycemic control. Semaglutide was introduced (0.25 mg weekly increased to 0.5 mg weekly) and was well tolerated. After 6 months, weight had decreased by 16 kg and insulin dose by 36%. Despite less insulin, hemoglobin A1c improved, with reduced glycemic variability and no increase in hypoglycemia. Semaglutide may exert significant metabolic benefits in patients with established T1DM, even where c-peptide is no longer detectable. This case supports the need for a dedicated trial examining potential benefits of semaglutide in T1DM.

Associations of Type 2 Diabetes, Body Composition, and Insulin Resistance with Bone Parameters: The Dubbo Osteoporosis Epidemiology Study.

Type 2 diabetes (T2D) may be associated with increased risk of fractures, despite preserved bone mineral density (BMD). Obesity and insulin resistance (IR) may have separate effects on bone turnover and bone strength, which contribute to skeletal fragility. We characterized and assessed the relative associations of obesity, body composition, IR, and T2D on bone turnover markers (BTMs), BMD, and advanced hip analysis (AHA). In this cross-sectional analysis of Dubbo Osteoporosis Epidemiology Study, 525 (61.3% women) participants were grouped according to T2D, IR (homeostasis model assessment insulin resistance [HOMA-IR]

Safety and tolerability of sodium-glucose cotransporter-2 inhibitors in bridge-to-transplant patients supported with centrifugal-flow left ventricular assist devices.

BACKGROUND: The safety and tolerability of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with end-stage heart failure supported with left-ventricular-assist-devices (LVADs), irrespective of diabetes mellitus, is not known. METHODS: A retrospective analysis of 31 outpatients implanted with LVADs as bridge-to-transplant (BTT) was conducted. Patients with biventricular support, aged under 18 years, who were discharged from the index hospitalisation, or were prescribed SGLT2i prior to their first outpatient clinic were excluded. Patient demographics, laboratory studies, pump haemodynamic and adverse event data was collected. RESULTS: Sixteen (51.6%) of 31 patients were prescribed SGLT2i over median 101.5 days (37.5-190.8). No patients discontinued SGLT2i use or reported attributable adverse symptoms. No significant differences between patients prescribed SGLT2i compared to those SGLT2i-naïve were seen in: [1] renal function; [2] weight; [3] mean arterial pressure. There were numerically lower infection-related (n = 4 vs 7, HR 0.32 (0.08-1.28), p = 0.11) and haemocompatibility-related (n = 3 vs 4, HR 0.52 (0.09-2.83), p = 0.45) adverse events in the SGLT2i group, albeit non-significant. CONCLUSIONS: We found SGLT2i to be safe and well-tolerated in the BTT LVAD cohort with no significant difference in rates of infection or haemocompatibility-related adverse events with SGLT2i use. Larger studies will inform further beneficial effects of SGLT2i prescription in this cohort.

Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014-2022).

PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.

Metabolic Sequelae of Everolimus Treatment After Cardiac Transplant: A Hypothesis-Generating Study.

BACKGROUND: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. METHODS: Post-hoc analysis to compare PTDM and other metabolic outcomes in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients (RADTAC1 study). RESULTS: There were 39 participants in the trial; mean follow-up was 6.4±1.5 years. There was a high rate of pre-existing diabetes (26%) and newly diagnosed PTDM (36%) during follow-up. Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). In the first 12 months there was a higher use of non-insulin treatment for diabetes in the everolimus-tacrolimus group compared to the standard tacrolimus group. CONCLUSIONS: This study suggests that treatment with everolimus may be associated with improved glycaemic control of PTDM relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Effects of bariatric surgery and dietary intervention on insulin resistance and appetite hormones over a 3 year period.

To examine an impact of three types of bariatric surgery compared with dietary intervention (DIET), on concurrent changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and appetite hormones over 3 years. Fifty-five adults were studied during phase of weight loss (0-12 months) and during weight stability (12-36 months) post intervention. Measurements of HOMA-IR, fasting and postprandial PYY and GLP1, adiponectin, CRP, RBP4, FGF21 hormones and dual-Xray absorptiometry were performed throughout the study. All surgical groups achieved significant reductions in HOMA-IR with greatest difference between Roux-en-Y gastric bypass and DIET (- 3.7; 95% CI - 5.4, - 2.1; p = 0.001) at 12-36 months. Initial (0-12 months) HOMA-IR values were no different to DIET after adjustment for the lost weight. During 12-36 months, after controlling for treatment procedure and weight, for every twofold increase in postprandial PYY and adiponectin, HOMA-IR decreased by 0.91 (95% CI - 1.71, - 0.11; p = 0.030) and by 0.59 (95% CI - 1.10, - 0.10; p = 0.023) respectively. Initial, non-sustained changes in RBP4 and FGF21 were not associated with HOMA-IR values. While initial rapid weight loss reduces insulin resistance, the enhanced secretions of PYY and adiponectin may contribute to weight-independent improvements in HOMA-IR during weight stability.Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000188730.

Sodium glucose co-transporter 2 inhibition with empagliflozin on metabolic, cardiac and renal outcomes in recent cardiac transplant recipients (EMPA-HTx): protocol for a randomised controlled trial.

INTRODUCTION: Cardiac transplantation (CTx) is a life-saving operation that can improve the quality and length of a recipient's life. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant complications include metabolic effects such as diabetes and weight gain, renal impairment, and cardiac disease such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of oral medication that increase urinary excretion of glucose. In patients with type 2 diabetes, SGLT2 inhibitors improve cardiovascular, metabolic and renal outcomes. Similar benefits have been shown in patients with heart failure and reduced ejection fraction irrespective of diabetes status. In patients with post-transplant diabetes mellitus, SGLT2 inhibitors improve metabolic parameters; however, their benefit and safety have not been evaluated in randomised prospective studies. This study will potentially provide a novel therapy to improve or prevent complications (diabetes, kidney failure and heart fibrosis) that occur with immunosuppressive medications. METHODS: The EMPA-HTx study is a randomised, placebo-controlled trial of the SGLT2 inhibitor empagliflozin 10 mg daily versus placebo in recent CTx recipients. One hundred participants will be randomised 1:1 and commence the study medication within 6-8 weeks of transplantation with treatment and follow-up until 12 months after transplantation. Demographic information, anthropomorphic measurements, pathology tests and cardiac magnetic resonance (CMR) scan will be recorded at baseline and follow-up. Patients will be reviewed monthly during the study until 12 months post-CTx and data will be collected for each patient at each study visit. The overall aim of the study is to assess the safety and efficacy of empagliflozin in CTx recipients. The primary outcome is glycaemic improvement measured as change in glycated haemoglobin and/or fructosamine. Key secondary outcomes are cardiac interstitial fibrosis measured by CMR and renal function measured by estimated glomerular filtration rate. ETHICS AND DISSEMINATION: This study has been approved by St Vincent's Hospital Human Research Ethics Committee (2021/ETH12184). The findings will be presented at national and international scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12622000978763.

Olanzapine-induced multifactorial chylomicronaemia syndrome: a rare but important complication.

Summary: We present a case of a 42-year-old man who developed acute onset severe hypertriglyceridaemia within days of commencing olanzapine therapy. Despite having a family history of metabolic syndrome, he had no personal history of hyperlipidaemia and had normal fasting lipids 1 week prior to treatment initiation. His case is consistent with a diagnosis of multifactorial chylomicronaemia syndrome with a possible undiagnosed underlying genetic lipid metabolism disorder. Our case highlights the difficulty in identifying patients at risk of severe hypertriglyceridaemia prior to the commencement of olanzapine. Learning points: Atypical antipsychotic medications, in particular olanzapine and clozapine, are associated with metabolic side effects. Olanzapine can precipitate acute onset severe hypertriglyceridaemia consistent with multifactorial chylomicronaemia syndrome. It is difficult to predict individuals at risk of olanzapine-induced hypertriglyceridaemia. This case demonstrates the importance of metabolic screening prior to the commencement of olanzapine and the possibility of repeating fasting serum lipids soon thereafter.