Impact of preoperative haemoglobin A1c levels on postoperative outcomes in adults undergoing major noncardiac surgery: A systematic review.

AIMS: Diabetes is known to increase morbidity and mortality after major surgery. However, literature is conflicting on whether elevated preoperative haemoglobin A1c (HbA1c) levels are associated with worse outcomes following major noncardiac surgery. We aimed to investigate the effect of incremental preoperative HbA1c levels on postoperative outcomes in adults who had undergone major noncardiac surgery. METHODS: We systematically searched PubMed, EMBASE and the Cochrane Library databases for eligible studies published between January 2012 and July 2023. Randomised controlled trials and observational studies (cohort and case-control studies) which measured HbA1c within 6 months before surgery and compared outcomes between at least three incremental subgroups or analysed HbA1c as a continuous variable were included. The systematic review protocol was registered with PROSPERO (CRD42023391946). RESULTS: Twenty observational studies investigating outcomes across multiple surgical types were included. Higher preoperative HbA1c levels were associated with increased odds of overall postoperative complications, postoperative acute kidney injury, anastomotic leak, surgical site infections and increased length of stay. Each 1% increase in preoperative HbA1c was associated with increased odds of these complications. No association with reoperations and 30-day mortality was identified. The literature was highly variable with respect to composite major complications, perioperative cardiovascular events, hospital readmissions, postoperative pneumonia and systemic thromboembolism. CONCLUSIONS: Current evidence suggested that higher preoperative HbA1c levels were associated with increased odds of postoperative complications and extended length of stay in adults undergoing major noncardiac surgery. Further high-quality studies would be needed to quantify the risks posed and determine whether early intervention improves outcomes.

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.

Gestational diabetes mellitus screening and diagnosis criteria before and during the COVID-19 pandemic: a retrospective pre-post study.

OBJECTIVE: To determine whether perinatal outcomes after excluding gestational diabetes mellitus (GDM) on the basis of fasting venous plasma glucose (FVPG) assessment during the coronavirus disease 2019 (COVID-19) pandemic in 2020 were similar to those during the preceding year after excluding GDM using the standard oral glucose tolerance test (OGTT) procedure. DESIGN: Retrospective pre-post study. SETTING, PARTICIPANTS: All women who gave birth in Queensland during 1 July - 31 December 2019 and 1 July - 31 December 2020. MAIN OUTCOME MEASURES: Perinatal (maternal and neonatal) outcomes for pregnant women assessed for GDM, by assessment method (2019: OGTT/glycated haemoglobin [HbA1c ] assessment; 2020: GDM could be excluded by an FVPG value below 4.7 mmol/L). RESULTS: 3968 of 29 113 pregnant women in Queensland during 1 July - 31 December 2019 (13.6%) were diagnosed with GDM, and 4029 of 28 778 during 1 July - 31 December 2020 (14.0%). In 2020, FVPG assessments established GDM in 216 women (1.1%) and excluded it in 1660 (5.8%). The frequencies of most perinatal outcomes were similar for women without GDM in 2019 and those for whom it was excluded in 2020 on the basis of FVPG values; the exception was caesarean delivery, for which the estimated probability increase in 2020 was 3.9 percentage points (95% credibility interval, 2.2-5.6 percentage points), corresponding to an extra 6.5 caesarean deliveries per 1000 births. The probabilities of several outcomes - respiratory distress, neonatal intensive care or special nursery admission, large for gestational age babies - were about one percentage point higher for women without GDM in 2020 (excluding those diagnosed on the basis of FVPG assessment alone) than for women without GDM in 2019. CONCLUSIONS: Identifying women at low absolute risk of gestational diabetes-related pregnancy complications on the basis of FVPG assessment as an initial step in GDM screening could reduce the burden for pregnant women and save the health system substantial costs.

Transthyretin binds soluble endoglin and increases its uptake by hepatocytes: A possible role for transthyretin in preeclampsia?

BACKGROUND: Preeclampsia is a common but life-threatening condition of pregnancy. It is caused by poor placentation resulting in release of trophoblast material (including soluble endoglin (sEng)) into the maternal circulation leading to maternal vascular dysfunction and to the life-threatening condition of eclampsia. The only cure is early delivery, which can have lifelong consequences for the premature child. The thyroid hormone binding protein transthyretin is dysregulated in preeclampsia, however it is not known if this plays a role in disease pathology. We hypothesised that transthyretin may bind sEng and abrogate its negative effects by removing it from the maternal serum. METHODS: The effect of transthyretin on hepatocyte uptake of Alexa-labelled sEng was measured using live cell imaging. Interactions between transthyretin, and sEng were investigated using molecular modelling, direct binding on CnBr Sepharose columns, confocal imaging, and measurement of fluorescence resonance energy transfer. RESULTS: Transthyretin directly bound to sEng and increased its uptake by hepatocytes. This uptake was altered in the presence of transforming growth factor-ß1 (TGF-ß1). Molecular modelling predicted that transthyretin and TGF-ß1 bind at the same site in sEng and may compete for binding. Endocytosed transthyretin and endoglin entered cells together and co-localised inside hepatocyte cells. CONCLUSION: Transthyretin can bind sEng and increase its uptake from the extracellular medium. This suggests that increasing transthyretin levels or developing drugs that normalise or mimic transthyretin, may provide treatment options to reduce sEng induced vascular dysfunction.

Cardiovascular disease management in Australian adults with type 2 diabetes: insights from the CAPTURE study.

BACKGROUND: Type 2 diabetes (T2D) is a well-recognised cardiovascular disease (CVD) risk factor, and recent guidelines for the management of T2D include consideration of CVD risk. AIM: To assess whether contemporary clinical management of Australians with T2D is in accord with recent national and international guidelines. METHODS: This Australia-specific analysis of the CAPTURE study, a non-interventional, cross-sectional study included adults diagnosed with T2D ≥180 days prior to providing informed consent and visiting primary or specialist care. Main outcome measures were the use of blood glucose-lowering medications (BGLMs), BGLMs with proven cardiovascular benefits and other CVD medications, stratified by CVD status and care setting. RESULTS: Of 824 Australian participants in the CAPTURE sample, 332 (40.3%) had CVD. Oral BGLMs were used by 83.9% of all participants, most commonly metformin (76.0%), dipeptidyl peptidase-4 inhibitors (28.8%), sodium-glucose cotransporter-2 inhibitors (SGLT2is; 21.8%) and sulfonylureas (21.7%). Insulin was used by 29.2% of participants. BGLMs with proven CV benefit were used by 22.6%; glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were less commonly used than SGLT2is in all CVD groups, but these drug classes were more often prescribed in specialist than primary care (SGLT2is 25.4 vs 20.7%, GLP-1 RAs 3.2 vs 0.8% respectively). Use of non-BGLMs for CVD risk reduction appeared consistent with guidelines. CONCLUSIONS: Use of BGLMs with CVD benefits appears low in Australia, irrespective of CVD status. This likely reflects the delay in translation of clinical evidence into contemporary care and prescribing restrictions.

Gestational diabetes screening from the perspective of consumers: Insights from early in the COVID-19 pandemic and opportunities to optimise experiences.

BACKGROUND: Consumer perspectives are a cornerstone of value-based healthcare. Screening and diagnosis of gestational diabetes mellitus (GDM) were among many of the rapid changes to health care recommended during the COVID-19 pandemic. The changes provided a unique opportunity to add information about women's perspectives on the debate on GDM screening. AIMS: The aim of this qualitative study was to explore women's perspectives and understanding of GDM screening and diagnosis comparing the modified COVID-19 recommendations to standard GDM screening and diagnostic practices. METHODS: Women who had experienced both the standard and modified GDM screening and diagnostic processes were recruited for telephone interviews. Data analysis used inductive reflexive thematic analysis. Online surveys were disseminated to any registrant not included in interviews to provide an opportunity for all interested participants to provide their perspective. RESULTS: Twenty-nine telephone interviews were conducted and 19 survey responses were received. Seven themes were determined: (1) information provision from clinicians; (2) acceptability of GDM screening; (3) individualisation of GDM screening methods; (4) safety nets to avoid a missed diagnosis; (5) informed decision making; (6) women want information and evidence; and (7) preferred GDM screening methods for the future. CONCLUSIONS: Overall, women preferred the modified GDM screening recommendations put in place due to the COVID-19 pandemic. However, their preference was influenced by their prior screening experience and perception of personal risk profile. Women expressed a strong need for clear communication from health professionals and the opportunity to be active participants in decision making.

Clinicians' perspectives on gestational diabetes screening during the global COVID-19 pandemic in Australia.

AIM: There is no international consensus for the screening and diagnosis of gestational diabetes mellitus (GDM). In March 2020, modified screening and diagnostic recommendations were rapidly implemented in Queensland, Australia, in response to the COVID-19 pandemic. How clinicians perceived and used these changes can provide insights to support high-quality clinical practice and provide lessons for future policy changes. The aim of this study was to understand clinicians' perceptions and use of COVID-19 changes to GDM screening and diagnostic recommendations. METHODS: Queensland healthcare professionals responsible for diagnosing or caring for women with GDM were recruited for semi-structured telephone interviews. Data analysis of transcribed interviews used inductive reflexive thematic analysis. RESULTS: Seventeen interviews were conducted with the following participants: six midwives/nurses, three endocrinologists, two general practitioners, two general practitioners/obstetricians, two diabetes educators, one dietitian and one obstetrician. Three themes emerged: communication and implementation, perceptions and value of evidence and diversity in perceptions of GDM screening. Overall, clinicians welcomed the rapid changes during the initial uncertainty of the pandemic, but as COVID-19 became less of a threat to the Queensland healthcare system, some questioned the underlying evidence base. In areas where GDM was more prevalent, clinicians more frequently worried about missed diagnoses, whereas others who felt that overdiagnosis had occurred in the past continued to support the changes. CONCLUSIONS: These findings highlight the challenges to changing policy when clinicians have diverse (and often strongly held) views.

Nicotine binds to the transthyretin-thyroxine complex and reduces its uptake by placental trophoblasts.

BACKGROUND: A supply of maternal thyroid hormone (thyroxine, T4) is essential for normal human fetal development. Human placental trophoblasts synthesize, secrete and take up the T4 binding protein transthyretin, providing a route for maternal T4 to enter the placenta. Transthyretin is also involved in T4 transport in other tissues such as the brain choroid plexus. Nicotine alters transthyretin synthesis and function in rat choroid plexus. If nicotine influences trophoblast turnover of transthyretin, then it may directly affect placental transfer of T4 to the developing fetus and contribute to the negative impacts of smoking on fetal growth, development and placental function. METHODS: The effect of nicotine on trophoblast uptake of Alexa-labelled transthyretin was measured using live cell imaging. The effect of nicotine on protein expression was measured by western blotting. Interactions between transthyretin, T4 and nicotine were investigated using chemical cross-linking techniques and molecular dynamic simulations. RESULTS: Nicotine blocks uptake of transthyretin-T4 by human placental trophoblast cells. Nicotine reduces the expression of the trophoblast scavenger receptor class B type 1 (SR-B1) that plays a role in transthyretin-T4 uptake. Molecular dynamic modelling suggests that when T4 is bound to transthyretin, nicotine binding increases tetramer stability, reducing the ability of the transthyretin-T4 complex to enter trophoblast cells. CONCLUSION: Our data suggest that nicotine exposure during pregnancy reduces transplacental transport of transthyretin and T4 to the placenta and developing fetus. This may contribute to the negative effects of smoking on fetal growth, development and pregnancy viability.

Capillary Triglycerides in Late Pregnancy-Challenging to Measure, Hard to Interpret: A Cohort Study of Practicality.

BACKGROUND: Maternal triglycerides are increasingly recognised as important predictors of infant growth and fat mass. The variability of triglyceride patterns during the day and their relationship to dietary intake in women in late pregnancy have not been explored. This prospective cohort study aimed to examine the utility of monitoring capillary triglycerides in women in late pregnancy. METHODS: Twenty-nine women (22 with gestational diabetes (GDM) and 7 without) measured capillary glucose and triglycerides using standard meters at home for four days. On two of those days, they consumed one of two standard isocaloric breakfast meals: a high-fat/low-carbohydrate meal (66% fat) or low fat/high carbohydrate meal (10% fat). Following the standard meals, glucose and triglyceride levels were monitored. RESULTS: Median capillary triglycerides were highly variable between women but did not differ between GDM and normoglycaemic women. There was variability in capillary triglycerides over four days of home monitoring and a difference in incremental area under the curve for capillary triglycerides and glucose between the two standard meals. The high-fat standard meal lowered the incremental area under the curve for capillary glucose (p < 0.0001). Fasting (rho 0.66, p = 0.0002) and postpradial capillary triglycerides measured at home correlated with venous triglyceride levels. CONCLUSIONS: The lack of differences in response to dietary fat intake and the correlation between capillary and venous triglycerides suggest that monitoring of capillary triglycerides before and after meals in pregnancy is unlikely to be useful in the routine clinical practice management of women with gestational diabetes mellitus.

Development of a fasting blood glucose-based strategy to diagnose women with gestational diabetes mellitus at increased risk of adverse outcomes in a COVID-19 environment.

OBJECTIVE: To evaluate the role of fasting blood glucose (FBG) to minimise the use of the oral glucose tolerance test in pregnancy (POGTT) for the diagnosis of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We analysed the POGTTs of 26,242 pregnant women in Queensland, Australia, performed between 1 January 2015 and 30 June 2015. A receiver operator characteristics (ROC) assessment was undertaken to indicate the FBG level that most effectively identified women at low risk of an abnormal result. RESULTS: There were 3,946 (15.0%) patients having GDM with 2,262 (8.6%) having FBG ≥ 5.1mmol/l. The ROC identified FBG levels >4.6mmol/l having the best specificity (77%) and sensitivity (54%) for elevated 1 and/or 2hr BGLs. There were 19,321 (73.7%) women having FBG < 4.7mmol/l with a prevalence of GDM of 4.0%, less than 1/3rd the overall rate. Only 4,638 (17.7%) women having FBGs from 4.7-5.0mmol/l would require further evaluation to confirm or exclude the diagnosis. CONCLUSION: This contemporary study of women across the state of Queensland, Australia suggests the FBG can be used effectively to define glucose tolerance in pregnancy, minimising their contact with pathology laboratories and potential exposure to the corona virus. This analysis, used in conjunction with outcome data from the HAPO study, provides reassurance to women and their health professionals that FBG < 4.7mmol/l has both a low rate of abnormal glucose tolerance and minimal adverse pregnancy-associated complications.

Effects of Changing Diagnostic Criteria for Gestational Diabetes Mellitus in Queensland, Australia.

OBJECTIVE: To evaluate the effects of updated gestational diabetes mellitus (GDM) screening and diagnostic criteria on selected perinatal outcomes in Queensland, Australia. METHODS: This was a pre-post comparison study using perinatal data the year before (2014) and after (2016) the screening and diagnostic criteria for GDM was changed in Queensland, Australia. In 2015, Queensland adopted the one-step screening and diagnostic criteria based on the International Association of the Diabetes and Pregnancy Study Groups' recommendations. The data from 62,517 women in 2014 and 61,600 women in 2016 who gave birth from 24 weeks of gestation were analyzed in three groups in each year: women with GDM; women without diagnosed GDM; and total population. The outcome measures were gestational hypertension, cesarean birth, gestational age at delivery, birth weight, preterm delivery, large-for-gestational age (LGA) neonates, small-for-gestational-age (SGA) neonates, neonatal hypoglycemia, and respiratory distress. RESULTS: The diagnosis of GDM increased from 8.7% (n=5,462) to 11.9% (n=7,317). After changing the diagnostic criteria, the changes to outcomes, odds ratios (OR), and adjusted odds ratios (aOR) (95% CI) for outcomes with statistically significant differences for the total population were: gestational hypertension 4.6% vs 5.0%, OR 1.09 (1.03-1.15), aOR 1.07 (1.02-1.13); preterm birth 7.6% vs 8.0%, OR 1.05 (1.01-1.09), aOR 1.06 (1.02-1.10); neonatal hypoglycemia 5.3% vs 6.8%, OR 1.31 (1.25-1.37), aOR 1.32 (1.25-1.38); and respiratory distress 6.2% vs 6.0%, OR 0.96 (0.91-1.00), aOR 0.94 (0.89-0.99). There was no change to cesarean births or LGA or SGA neonates for women with or without diagnosed GDM or the total population. CONCLUSION: Except for a very small decrease in respiratory distress, changing the diagnostic criteria has resulted in more GDM diagnoses with no observed changes to measured perinatal outcomes for women with and without diagnosed GDM.

Hyponatraemia in heart failure.

Hyponatraemia is common in heart failure (HF). It is estimated that over 20% of patients admitted to hospital with HF have hyponatraemia. It has also been repeatedly shown to be a surrogate marker of increased morbidity and mortality in this specific population. This review focuses on the pathophysiology of hyponatraemia through the activation of neurohormonal cascades in HF, the clinical implications of sustained hyponatraemia and treatment options in the management of this challenging phenomenon.

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.

Scavenger Receptor Class B Member 1 Independent Uptake of Transthyretin by Cultured Hepatocytes Is Regulated by High Density Lipoprotein.

Thyroid hormone (thyroxine, T4) is essential for the normal function of all cell types and is carried in serum bound to several proteins including transthyretin. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. Transthyretin and transthyretin bound T4 are endocytosed by placental trophoblasts through the high-density lipoprotein receptor, Scavenger Receptor Class B Type 1 (SR-B1). High density lipoprotein (HDL) affects the expression and function of SR-B1 in trophoblast cells. SR-B1 is also expressed in hepatocytes and we sought to determine if hepatocyte SR-B1 was involved in transthyretin or transthyretin-T4 uptake and whether uptake was affected by HDL. Transthyretin and transthyretin-T4 uptake by hepatocytes is not dependent on SR-B1. HDL treatment reduced SR-B1 expression. However, pretreatment of hepatocytes with HDL increased uptake of transthyretin-T4. Knockdown of SR-B1 expression using siRNA also increased transthyretin-T4 uptake. Coaddition of HDL to transthyretin uptake experiments blocked both transthyretin and transthyretin-T4 uptake. Hepatocyte uptake of transthyretin-T4 uptake is influenced by, but is not dependent on, SR-B1 expression. HDL also decreases transthyretin-T4 uptake and therefore diet or drugs may interfere with this process. This suggests that multiple lipoprotein receptors may be involved in the regulation of uptake of transthyretin-T4 in a cell-type specific manner. Further study is required to understand this important process.

Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study.

BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481. FINDINGS: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20·2% (95% CI 19·9-20·5) during the 6-week active fenofibrate run-in period immediately pre-randomisation (a reduction of 0·06 mmol/L or 1 mg/dL) and remained -20·1% (18·5-21·7, p<0·0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0·54, 95% CI 0·41-0·70; p<0·0001). In the placebo group, the cumulative proportion of patients with first gout events was 7·7% in patients with baseline uric acid concentration higher than 0·36 mmol/L and 13·9% in those with baseline uric acid concentration higher than 0·42 mmol/L, compared with 3·4% and 5·7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0·48, 95% CI 0·37-0·60; p<0·0001) compared with placebo. INTERPRETATION: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes. FUNDING: None.

Transthyretin uptake in placental cells is regulated by the high-density lipoprotein receptor, scavenger receptor class B member 1.

Transfer of thyroid hormone into cells is critical for normal physiology and transplacental transfer of maternal thyroid hormones is essential for normal fetal growth and development. Free thyroid hormone is known to enter cells through specific cell surface transport proteins, and for many years this uptake of unbound thyroid hormones was assumed to be the only relevant mechanism. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. In this study we identify the high-density lipoprotein receptor Scavenger Receptor class B member 1 (SR-B1) as important in the uptake and transport of transthyretin-bound thyroid hormone by placental trophoblast cells. High-density lipoprotein increases expression of SR-B1 in placental cells but also reduces uptake of transthyretin-thyroid hormone through the SR-B1 transporter. SR-B1 is expressed in many cells and this study suggests that SR-B1 may be universally important in thyroid hormone uptake. Further investigation of SR-B1-TTR interactions may fundamentally change our understanding of hormone biology and have important clinical consequences.

SGLT2 inhibitors with cardiovascular benefits: Transforming clinical care in Type 2 diabetes mellitus.

Cardiovascular risk reduction in individuals with Type 2 diabetes mellitus (T2DM) is a key part of clinical management. Sodium-glucose co-transporter (SGLT2) inhibitors improve glycaemic control, reduce body weight and decrease blood pressure. In addition, the SGLT2 inhibitors empagliflozin and canagliflozin reduced the risk of composite cardiovascular events in high-risk individuals with T2DM in the EMPA-REG OUTCOME trial and the CANVAS Program, respectively. Empagliflozin also reduced cardiovascular deaths and improved renal outcomes. This class of agents should be considered in people with established cardiovascular disease, usually in combination with other glucose lowering medications, when satisfactory glycaemic control has not been achieved. The dose of insulin or sulfonylureas may need to be lowered when used with SGLT2 inhibitors, to reduce the risk of hypoglycaemia. Genitourinary infections can occur with SGLT2 inhibitors in a small proportion of people. In people with osteoporosis or prior amputation, it may be prudent to use empagliflozin rather than canagliflozin, based on the increased risk for bone fractures and amputations observed with canagliflozin in the CANVAS Program. SGLT2 inhibitors have the potential to transform the clinical care of persons with T2DM by not only improving glycaemic control but also reducing blood pressure, body weight and diabetes-related end-organ complications.

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice-daily basal insulin to once-daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis).

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference -0.01%; 95% confidence interval [CI] -0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI -0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00-05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin.