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Aim To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and Methods Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL-related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal-specific outcome by baseline AF/AFL status were analysed using Cox regression models. Results Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67-1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62-0.99). Canagliflozin was also associated with a reduction in AF/AFL-related complications (HR 0.74, 95% CI 0.65-0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all P-interaction > 0.14). Meta-analysis of five sodium-glucose cotransporter-2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72-0.92). Conclusions Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta-analysis suggests SGLT2 inhibition reduces AF/AFL incidence.

BACKGROUND We aimed to determine risk factors for incident CKD in a large population-based cohort. METHODS This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia enrolment database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely-collected databases. The primary outcome was the development of incident CKD, defined as eGFR

Background Sex and gender differences in chronic kidney disease (CKD), including epidemiology and response to treatment, remain poorly understood. This study aimed to investigate how women are represented in CKD clinical trials and whether sex- and gender-disaggregated outcomes were reported. Methods Clinical trials on CKD were identified from ClinicalTrials.gov. Randomised, phase 3/4 trials with ≥100 participants were selected to quantify women's representation among participants by computing the participation:prevalence ratio (PPR) and investigating whether sex-disaggregated analyses had been performed. Results In total, 192 CKD trials registered on ClinicalTrials.gov and published between 1995 and 2022 were included. Overall, women accounted for 66 875 (45%) of the 147 136 participants. Women's participation in clinical trials was lower than their representation in the underlying CKD population globally (55%). The PPR was 0.75 (95% confidence interval 0.72–0.78), with no significant variation irrespective of mean age, CKD stage, dialysis, location, type of intervention or funding agency. A total of 39 (20%) trials reported sex-disaggregated efficacy outcomes and none reported sex-disaggregated safety outcomes. Conclusion Women's participation in CKD clinical trials was lower than their representation in the underlying CKD population. Sex-disaggregated efficacy and safety outcomes were rarely reported. Improving women's enrolment into clinical trials is crucial to enable sex- and gender-disaggregated analysis and thus identify potential differences in treatment response between women and men.

Aims/hypothesis Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. Methods We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (16 years) and HbA1c (≤53.0 mmol/mol [53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance Results At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0–18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. Conclusions/interpretation In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c. Graphical abstract

Objective To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. Design CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. Setting 17 hospital sites in India and Australia. Participants Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. Intervention Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. Main outcome measures The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. Results Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. Conclusions In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. Trial registration ClinicalTrials.gov NCT04394117 .

Aims The aim of this study was to determine the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in adults with atrial fibrillation (AF) by level of kidney function. Methods and results We pooled findings from five retrospective cohorts (2011–18) across Australia and Canada of adults with; a new dispensation for a DOAC or warfarin, an AF diagnosis, and a measure of baseline estimated glomerular filtration rate (eGFR). The outcomes of interest, within 1 year from the cohort entry date, were: (1) the composite of all-cause death, first hospitalization for ischaemic stroke, or transient ischaemic attack (effectiveness), and (2) first hospitalization for major bleeding defined as an intracranial, upper or lower gastrointestinal, or other bleeding (safety). Cox models were used to examine the association of a DOAC vs. warfarin with outcomes, after 1:1 matching via a propensity score. Kidney function was categorized as eGFR ≥60, 45–59, 30–44, and Conclusion DOAC use, compared with warfarin use, was associated with a lower or similar risk of all-cause death, ischaemic stroke, and transient ischaemic attack and also a lower or similar risk of major bleeding across all levels of kidney function.

The COVID-19 pandemic has disrupted healthcare services around the world, which may have serious implications for the prognosis of patients with acute cardiovascular disease. We conducted a systematic review to assess the extent to which health services related to the care and management of acute cardiovascular events have been impacted during the COVID-19 pandemic. PubMed, MedRxiv, and Google Scholar were searched for observational studies published up to 12 August 2020 for studies that assessed the impact of the pandemic on the care and management of people with acute cardiovascular disease (CVD). In total, 27 articles were included. Of these, 16 examined the impact on acute coronary syndromes (ACS), eight on strokes, one on ACS and strokes, and two on other types of CVD. When comparing the COVID-19 period to non-COVID-19 periods, 11 studies observed a decrease in ACS admissions ranging between 40% and 50% and 5 studies showed a decrease in stroke admissions of between 12% and 40%. Four studies showed a larger reduction in non-ST-segment elevation myocardial infarctions compared to ST-segment elevation myocardial infarctions. A decrease in the number of reperfusion procedures, a shortening in the lengths of stay at the hospital, and longer symptom-to-door times were also observed. The COVID-19 pandemic has led to a substantial decrease in the rate of admissions for acute CVD, reductions in the number of procedures, shortened lengths of stay at the hospital, and longer delays between the onset of the symptoms and hospital treatment. The impact on patient’s prognosis needs to be quantified in future studies.

Background. The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. Methods. Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. Results. Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88–2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01–1.06), female sex (HR 2.49, CI 1.70–3.65), previous fracture (HR 2.30, CI 1.58–3.34), Asian race (HR 1.74, CI 1.09–2.78), vitamin D therapy requirement (HR 2.05, CI 1.31–3.21), HbA1c (HR 1.14, CI 1.00–1.32), prior cardiovascular event (HR 1.60, CI 1.10–2.33), and serum albumin (HR 0.41, CI 0.23–0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92–1849.51, SBC range 1875.60–1948.04). Conclusion. Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors.

Background Previous reports on the prevalence of chronic kidney disease (CKD) in Asia have suggested important sex disparities but have been inconsistent in nature. We sought to synthesize available sex-disaggregated CKD prevalence data in Asia to quantify sex disparities in the region. Methods We systematically searched MEDLINE and Embase for observational studies involving ≥500 adults who reported sex-disaggregated CKD prevalence data in any of the 26 countries in East, Southeast and South Asia. For each study we calculated the female:male prevalence ratio (PR), with a ratio >1 indicating a higher female prevalence. For each country, log-transformed PRs were pooled using random effects meta-analysis. These were then combined using a fixed effects model, weighting by population size, to estimate a pooled PR for each of East, Southeast and South Asia and Asia overall. Results Sex-disaggregated data were available from 171 cohorts, spanning 15 countries and comprising 2 550 169 females and 2 595 299 males. Most studies (75.4%) came from East Asia (China, Taiwan, Japan and South Korea). Across Asia, CKD prevalence was higher in females {pooled prevalence 13.0% [95% confidence interval (CI) 11.3–14.9]} compared with males [pooled prevalence 12.1% (95% CI 10.3–14.1)], with a pooled PR of 1.07 (95% CI 0.99–1.17). Substantial heterogeneity was observed between countries. The pooled PRs for East, Southeast and South Asia were 1.11 (95% CI 1.02–1.21), 1.09 (0.88–1.36) and 1.03 (0.87–1.22), respectively. Conclusions Current evidence suggests considerable between-country and -region heterogeneity in the female:male PR of CKD. However, there remains a large part of the region where data on sex-specific CKD prevalence are absent or limited. Country-level assessment of the differential burden of CKD in females and males is needed to define locally relevant policies that address the needs of both sexes.

IntroductionThe burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the variations in national prevalence within Asia. We aimed to consolidate available data and quantify estimates of the CKD burden in this region.MethodsWe systematically searched MEDLINE, Embase and Google Scholar for observational studies and contacted national experts to estimate CKD prevalence in countries of Asia (Eastern, Southern and South Eastern Asia). CKD was defined as estimated glomerular filtration rate (eGFR) 2 or the presence of proteinuria. For countries without reported data, we estimated CKD prevalence using agglomerative average-linkage hierarchical clustering, based on country-level risk factors and random effects meta-analysis within clusters. Published CKD prevalence data were obtained for 16 countries (of the 26 countries in the region) and estimates were made for 10 countries.ResultsThere was substantial variation in overall and advanced (eGFR 2) CKD prevalence (range: 7.0%–34.3% and 0.1%–17.0%, respectively). Up to an estimated 434.3 million (95% CI 350.2 to 519.7) adults have CKD in Asia, including up to 65.6 million (95% CI 42.2 to 94.9) who have advanced CKD. The greatest number of adults living with CKD were in China (up to 159.8 million, 95% CI 146.6 to 174.1) and India (up to 140.2 million, 95% CI 110.7 to 169.7), collectively having 69.1% of the total number of adults with CKD in the region.ConclusionThe large number of people with CKD, and the substantial number with advanced CKD, show the need for urgent collaborative action in Asia to prevent and manage CKD and its complications.

Stepwise escalation of glucose-lowering therapy to more intensive regimens is an integral component of type 2 diabetes management (1). Early blood glucose control is associated with beneficial effects on long-term micro- and macrovascular outcomes (2). Understanding factors associated with time to therapy escalation following an elevated glycated hemoglobin (HbA1c) may inform interventions to facilitate timely control. We used linked real-world data to examine time to therapy escalation following a recorded HbA1c ≥8.0% (64 mmol/mol) and associated factors. The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45 Study) is an Australian population-based linked data study in which participants of the 45 and Up Study have been linked to the Medicare Benefits Schedule (MBS), providing data on government-subsidized medical services, the Pharmaceutical Benefits Scheme (PBS), providing prescription claims data, and community laboratory databases (among others) (3). The 45 and Up Study comprises 267,153 individuals aged ≥45 years living in New South Wales (NSW), Australia, recruited between July 2006 and December 2009. Ethical approval for the EXTEND45 Study was obtained from the NSW Population & Health Services Research Ethics Committee (HREC/13/CIPHS/49). In EXTEND45, 24,430 individuals with diabetes between 2006 and 2014 have been identified using multiple linked data sources (3). In the current study, therapy escalation was assessed during the 6 months following all linked HbA1c results ≥8.0% occurring in non–treatment-naive, non–insulin-using individuals presumed to have type 2 diabetes. As a result, the unit of analysis was the elevated HbA1c, with individuals able to contribute multiple results to the analysis. A threshold of 8.0% was used to reflect the typically higher HbA1c targets recommended for older people (4). To ensure that all included HbA1c results represented separate instances of an elevated HbA1c in the same individual, those results ≥8.0% that occurred …

BACKGROUND AND OBJECTIVES: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to 300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to RESULTS: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to CONCLUSIONS: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov: CREDENCE, NCT02065791.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.

Background: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, –4.27 to –2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61–0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59–0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.

SummaryThe CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The CLARITY trial is a multi-centre, randomised controlled Bayesian adaptive trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here we describe the statistical analysis plan for the trial, and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at Day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov,NCT04394117. Registered on 19 May 2020.https://clinicaltrials.gov/ct2/show/NCT04394117Clinical Trial Registry of India: CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Background SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes. Methods and discussion CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020. Trial registration ClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)

Aims/hypothesis Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. Methods We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (16 years) and HbA1c (≤53.0 mmol/mol [53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0–18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. Conclusions/interpretation In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c. Graphical abstract Supplementary Information The online version of this article (10.1007/s00125-021-05524-1) contains peer-reviewed but unedited supplementary material.

Aims To use linked routinely-collected health data to estimate diabetes prevalence and incidence in an Australian cohort of adults aged ≥45 years, and examine risk factors associated with incident disease. Research design and methods The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45) Study is a linked data study that combines baseline questionnaire responses from the population-based 45 and Up Study (2006–2009, n = 267,153) with multiple routinely-collected health databases up to December 2014. Among participants with ≥1 linked result for any laboratory test, diabetes status was determined from multiple data sources according to standard biochemical criteria, use of glucose-lowering medication or self-report, and the prevalence and incidence rate calculated. Independent risk factors of incident diabetes were examined using multivariable Cox regression. Results Among 152,169 45 and Up Study participants with ≥1 linked laboratory result in the EXTEND45 database (mean age 63.0 years; 54.9% female), diabetes prevalence was 10.8% (95% confidence interval [CI] 10.6%–10.9%). Incident disease in those without diabetes at baseline (n = 135,810; mean age 62.5 years; 56.1% female) was 10.0 per 1,000 person-years (95% CI 9.8–10.2). In all age groups, diabetes incidence was lower in women compared to men, an association that persisted in the fully adjusted analyses. Other independent risk factors of diabetes were older age, being born outside of Australia (with the highest rate of 19.2 per 1,000 person-years observed in people born in South and Central Asia), lower education status, lower annual household income, residence in a major city, family history of diabetes, personal history of cardiovascular disease or hypertension, higher body mass index, smoking and long sleeping hours. Conclusions Our study represents an efficient approach to assessing diabetes frequency and its risk factors in the community. The infrastructure provided by the EXTEND45 Study will be useful for diabetes surveillance and examining other important clinical and epidemiological questions.

Stepwise escalation of glucose-lowering therapy to more intensive regimens is an integral component of type 2 diabetes management (1). Early blood glucose control is associated with beneficial effects on long-term micro- and macrovascular outcomes (2). Understanding factors associated with time to therapy escalation following an elevated glycated hemoglobin (HbA1c) may inform interventions to facilitate timely control. We used linked real-world data to examine time to therapy escalation following a recorded HbA1c ≥8.0% (64 mmol/mol) and associated factors.

Background and Aims Patient with type 2 diabetes mellitus (T2DM) included in trials of sodium-glucose cotransporter 2 inhibitors are heterogeneous in terms of disease severity. We assessed the effects of canagliflozin compared to placebo on cardiovascular and renal outcomes in the CANVAS program according to severity of T2DM as indicated by intensity of treatment, duration of diabetes and glycaemic control. Method We compared effects on major adverse cardiovascular events ([MACE], defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) according to three indicators of T2DM severity at study baseline: number of oral glucose lowering treatments or insulin therapy (0-1, 2, 3+, insulin), duration of diabetes (16 years) and HbA1c (9.0%). We also assessed effects on other pre-specified cardiovascular outcomes, and an adjudicated composite of end-stage kidney disease, renal death or sustained 40% decline in estimated glomerular filtration rate. We assessed for constancy of hazard ratios across subgroups by fitting an interaction term that tested for linear trend. Results Of 10,142 participants in the CANVAS Program, 1011 experienced a MACE during a mean follow-up of 3.6 years. Event rates for MACE were higher in those with longer duration of diabetes and higher HbA1c at baseline. The effect of canagliflozin on MACE in the overall population (HR 0.86, 95 % CI 0.75-0.97) was consistent irrespective of the number of glucose lowering treatments (p=0.509), duration of diabetes (p=0.174) and baseline HbA1c (p =0.314). Effects were also consistent across different levels of T2DM disease severity for all other outcomes studied. Conclusion Higher event rates were observed in those with longer disease duration and higher HbA1c. The proportional risk reductions achieved with canagliflozin were comparable regardless of diabetes duration, number of therapies or HbA1C at baseline.

Background and Aims To describe genital mycotic infections (GMI) and urinary tract infections (UTI) in the CREDENCE trial, determine whether canagliflozin increased the risk of these infections overall and in subgroups, and describe predictors of risk for genital mycotic infections. Method The CREDENCE trial randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to canagliflozin 100mg daily or placebo. We analysed the risk of GMI and UTI with canagliflozin compared to placebo overall and in patient subgroups. The primary analysis was conducted in the on-treatment population, as the more conservative approach with sensitivity analyses conducted using an intention-to-treat population. When canagliflozin increased risk, we determined patient risk factors for GMIs using multivariable Cox regression models adjusting for age, gender, race, markers of disease severity (body mass index (BMI), haemoglobin A1c, diabetes duration, other glucose lowering medications at baseline and kidney function). Results Overall 31/2905 (1.1%) men and 32/1492 (2.1%) women experienced 91 GMIs and 166/2905 (5.7%) men and 300/1492 (20.1%) women experienced 669 UTIs. Canagliflozin increased the risk of GMI (HR 3.83 [95% CI 2.08-7.06] p Conclusion Canagliflozin increased the risk of genital mycotic infections but not urinary tract infections. The risk of genital mycotic infections from canagliflozin over placebo was higher in men and those with higher BMI. In those treated with canagliflozin, higher BMI and longer diabetes duration independently predicted infection. Most participants continued treatment following their first infection with similar recurrence rates in the canagliflozin and placebo groups.These findings will be useful in clinical care, and help identify those at greatest risk for genital infections with canagliflozin treatment.

Background and Aims The skin’s hypertonic microenvironment has a hypothesized protective antimicrobial function that may be disrupted by SGLT2i. The association between sodium glucose cotransporter inhibitors (SGLT2i) and genital mycotic infections is well established, but it is not known if these agents increase the risk of other skin and soft tissue infections (SSTI). We aimed to describe SSTI in the CREDENCE trial, and determine whether canagliflozin affects the risk of skin and soft tissue infections (SSTIs) overall and in subgroups. Method We performed a post-hoc analysis of the CREDENCE trial that randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to either canagliflozin 100mg daily or placebo. Infections reported as adverse events were assessed by two blinded authors following predetermined criteria for SSTI with discrepancies resolved by consensus. We analysed the risks of SSTIs in the on-treatment population as the more conservative approach, with a sensitivity analysis conducted in the intention-to-treat population. Univariable time-to first-event regression models were assessed. Results Overall 373/4397 (8.5%) participants experienced 478 events comprising 252 bacterial skin infections (including 2 episodes of necrotising fasciitis), 94 fungal skin infections, 109 other skin infections and 23 soft tissue infections. Of these, 136/478 (28%) were serious. Drug was continued in 290/373 (78%) of first events, with similar frequency of subsequent events between groups (31/133 (23%) and 33/157 (21%) for those continuing canagliflozin and placebo respectively). In both cases of necrotising fasciitis, drug was withdrawn and the participants recovered.Canagliflozin did not increase the risk of SSTI (HR 0.85 [95% Confidence Interval (CI) 0.69-1.04] p=0.11) (Figure 1). Results were similar in the intention-to-treat population (HR 0.88 [95% CI 0.73-1.07] p=0.20), in analyses confined to serious SSTI (HR 0.83 [95% CI 0.58-1.21] p=0.33), and in the predefined subgroups. Conclusion Although other studies suggest that SGLT2i may reduce the sodium content of the skin, we found that canagliflozin does not increase the risk of skin and soft tissue infections, overall or in any subgroup, in people with type 2 diabetes mellitus and albuminuric chronic kidney disease.

OBJECTIVE To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) RESEARCH DESIGN AND METHODS We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement RESULTS Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR CONCLUSIONS In participants with diabetes, the incidence of an eGFR

BACKGROUND Chronic kidney disease (CKD) and diabetes are the major causes of death and disability worldwide. They are associated with high health service utilization persisting over many years. Their slow progression and wide clinical variation make them eminently suitable for study in population-based cohorts. However, current understanding of their prevalence, incidence, and progression is largely based on studies conducted in clinical populations. OBJECTIVE This study aims to establish a novel link between an existing population-based cohort (the 45 and Up Study) and routinely collected laboratory and administrative data to facilitate research across the full disease spectrum of CKD and diabetes. METHODS In the EXTEND45 Study (EXamining OuTcomEs in chroNic Disease in the 45 and Up Study), baseline questionnaire responses of over 260,000 participants of the 45 and Up Study aged ≥45 years living in New South Wales (NSW), collected between January 2006 and December 2009, are linked to data from laboratory service providers as well as national- and state-based administrative datasets via probabilistic linkage. Routinely collected data were obtained for participants who could be linked between January 2005 and July 2013. Laboratory data will enable the identification of early cases of chronic disease and the assessment of clinically relevant biochemical targets during the disease course. Health administrative datasets will allow for the examination of health service use, pharmacological management, and clinical outcomes. RESULTS The study received ethics approval from the NSW Population and Health Services Research Ethics Committee in February 2014. Data linkage for 267,153 of the 45 and Up Study participants was completed in June 2016, with congruent linkage achieved for 265,086 (99.23%) individuals. To date, the CKD and diabetes cohorts have been identified (published elsewhere), and a diverse portfolio of research projects relating to disease burden, risk factors, health outcomes, and health service utilization is in development. CONCLUSIONS The EXTEND45 Study represents an unparalleled opportunity to perform extensive research into diseases of considerable public health and clinical importance. Strengths include the population-based nature of the cohort and the availability of longitudinal information on the complete disease pathway for affected individuals. INTERNATIONAL REGISTERED REPORT RR1-10.2196/15646

Background: Multiple regimens for the pharmacological management of diabetes exist. In Australia, new agents have become available in recent years. We examined temporal trends in prescribing patterns of pharmacotherapy regimens in Australia. Methods: The EXTEND45 Study links health information on consenting participants of the 45 and Up Study (2006-2009) with administrative health information from the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) (provided by the Department of Human Services), community pathology providers and other routinely collected health information sources. Linkage was performed by the Centre for Health Record Linkage and the Sax Institute (MBS and PBS). We identified a population-based cohort (2006-2014) of people aged ≥45 years who met a pre-specified definition for diabetes. Treatment episodes amongst our cohort were identified, and defined as the period that a patient adhered to a particular regimen of pharmacotherapy without any changes or treatment breaks of two or more standard coverage days (SCD). Episodes were attributed to the calendar year in which they commenced and were categorized into six patterns of glucose lowering medication use. Results: We identified 24,236 participants with diabetes who experienced 149,532 treatment episodes over a mean follow-up period of 4.97 years. Episodes included: never treated (4.4%), monotherapy (33.1%), dual therapy (17.0%), triple or more therapy (4.0%), insulin-based therapy (21.7%) and treatment break (20.3%). Metformin (a biguanide) accounted for the majority (68.5%) of monotherapy episodes, followed by sulfonlyureas (23.1%). The combination of metformin and a sulfonylurea was the most common dual therapy episode (56.1%) but became less common over the study period (75.5% in 2006 to 41.1% in 2014). Conclusion: Most treatment episodes in our cohort involved a monotherapy regimen. There was a temporal change in the specific drug agents prescribed in dual therapy regimens, likely related to the availability of newer agents. Disclosure T.K. Young: None. C. Hockham: None. L. Sukkar: None. A. Kang: None. M. Jun: Research Support; Self; AstraZeneca. J. Baker: None. K. Rogers: None. A. Cass: None. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Novartis AG, Vifor Pharma. Other Relationship; Self; Janssen Pharmaceuticals, Inc. D. Sullivan: None. G. Wong: None. M.J. Jardine: Advisory Panel; Self; Akebia Therapeutics, Baxter, Boehringer Ingelheim International GmbH, CSL Behring, Vifor Pharma. Research Support; Self; Amgen Inc., Baxter, Eli Lilly and Company, Gambro, Merck Sharp & Dohme Corp. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Heart Foundation of Australia (100720); Roche Products Pty Ltd. (FR-MIR-0095); Rebecca L. Cooper Grant (REB002); Eli Lilly Australia Pty Ltd. (PO4100294024); Merck Sharp & Dohme Australia Pty Ltd. (MSD_EXTEND45); Amgen Australia Pty Ltd. (Amgen01)

Background: Comparative, real-world evidence for clinical outcomes of different glucose lowering pharmacotherapy regimens in diabetes is limited. We compared therapy persistence and achieved HbA1c amongst episodes of different pharmacotherapy regimens in a community-based Australian cohort. Methods: The EXTEND45 Study combines baseline questionnaire responses (2006-2009) with data from community pathology providers, the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) (provided by the Department of Human Services) and other routinely collected health databases for participants of the 45 and Up study for the period 2005 to 2014. Linkage of MBS and PBS data was performed by the Sax Institute and all other data sources by the Centre for Health Record Linkage. We identified 24,236 people aged ≥45 years with diabetes. Using treatment episodes as our unit of analysis, the persistence and achieved glycaemic control of episodes was compared according to therapy regimens using Wilcoxon Sum rank tests. Results: Among 149,532 episodes, mean (median) therapy persistence was 163 (76), 175 (84), 132 (54) and 164 (108) days for mono-, dual, multioral-, and insulin-based therapy episodes, respectively. For monotherapy episodes, mean persistence was greatest for metformin (178 days). For dual therapy, mean persistence was longest for combinations that did not involve metformin or a sulfonylurea (195 days). Mean HbA1c was 6.9%, 7.3%, 7.4% and 7.9% for mono-, dual, multioral-, and insulin-based therapy episodes, respectively. For monotherapy episodes, mean HbA1c was lowest for metformin (6.8%) whilst for dual therapy, mean persistence was highest for sulfonylurea combinations that did not involve metformin (7.5%). Conclusion: Persistence with therapy is heterogeneous across different intensities of therapy and is shortest for multioral-agent regimens. Participants requiring insulin therapy have the highest achieved HbA1c, which is likely to reflect disease severity. Disclosure T.K. Young: None. C. Hockham: None. L. Sukkar: None. A. Kang: None. M. Jun: Research Support; Self; AstraZeneca. J. Baker: None. K. Rogers: None. A. Cass: None. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Novartis AG, Vifor Pharma. Other Relationship; Self; Janssen Pharmaceuticals, Inc. D. Sullivan: None. G. Wong: None. M.J. Jardine: Advisory Panel; Self; Akebia Therapeutics, Baxter, Boehringer Ingelheim International GmbH, CSL Behring, Vifor Pharma. Research Support; Self; Amgen Inc., Baxter, Eli Lilly and Company, Gambro, Merck Sharp & Dohme Corp. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Heart Foundation of Australia (100720); Roche Products Pty Ltd. (FR-MIR-0095); Rebecca L. Cooper Grant (REB002); Eli Lilly Australia Pty Ltd. (PO4100294024); Merck Sharp & Dohme Australia Pty Ltd. (MSD_EXTEND45); Amgen Australia Pty Ltd. (Amgen01)

Severe forms of α-thalassaemia, haemoglobin H disease and haemoglobin Bart’s hydrops fetalis, are an important public health concern in Southeast Asia. Yet information on the prevalence, genetic diversity and health burden of α-thalassaemia in the region remains limited. We compiled a geodatabase of α-thalassaemia prevalence and genetic diversity surveys and, using geostatistical modelling methods, generated the first continuous maps of α-thalassaemia mutations in Thailand and sub-national estimates of the number of newborns with severe forms in 2020. We also summarised the current evidence-base for α-thalassaemia prevalence and diversity for the region. We estimate that 3595 (95% credible interval 1,717–6,199) newborns will be born with severe α-thalassaemia in Thailand in 2020, which is considerably higher than previous estimates. Accurate, fine-scale epidemiological data are necessary to guide sustainable national and regional health policies for α-thalassaemia management. Our maps and newborn estimates are an important first step towards this aim.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).