Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease

When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g. iohexol clearance). In clinical practice measurement of creatinine and cystatin C is used in equations (e.g. Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) to provide estimated GFR. We studied biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 mL/min/1.73 m2). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously GFR was estimated using the MDRD, CKD-EPIcreatinine, CKD-EPIcystatinC and CKD-EPIcreatinine+cystatinC equations. Within-subject biological variation (CVI) expressed as a percentage [95% CI] for the MDRD (5.0% [4.3-6.1]), CKD-EPIcreatinine (5.3% [4.5-6.4]), CKD-EPIcystatinC (5.3% [4.5-6.5]), and CKD-EPIcreatinine+cystatinC (5.0% [4.3-6.2]) equations were broadly equivalent. CVI values for MDRD and CKD- EPIcreatinine+cystatinC were lower (p=0.027 and p=0.022 respectively) than that of measured GFR (6.7% [5.6-8.2]). Reference change values (RCV), the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated: using the MDRD equation, positive and negative RCVs were 15.1% and 13.1% respectively. If an individual’s baseline MDRD estimated GFR (mL/min/1.73 m2) was 59, significant increases or decreases would be to values >68 or <51 respectively. Within-subject variability of estimated GFR is lower than measured GFR. RCVs can be used to understand GFR changes in clinical practice

The Present & Future Scope of RWE Research in Diabetes: What Questions Can and Can’t Be Answered and What Might be Possible in the Future?

The last decade has witnessed an exponential growth in the opportunities to collect and link health-related data from multiple resources, including primary care, administrative, and device data. The availability of these “real-world”, “big data” has fuelled also an intense methodological research into methods to handle them and extract actionable information. In medicine, the evidence generated from “real-world data” (RWD), which are not purposely collected to answer biomedical questions, is commonly termed “real-world evidence” (RWE). In this review, we focus on RWD and RWE in the area of diabetes research, highlighting their contributions in the last decade; and give some suggestions for future RWE diabetes research, by applying well-established and less-known tools to direct RWE diabetes research towards better personalised approaches to diabetes care. We underline the essential aspects to consider when using RWD and the key features limiting the translational potential of RWD in generating high-quality and applicable RWE. Only if viewed in the context of other study designs and statistical methods, with its pros and cons carefully considered, RWE will exploit its full potential as a complementary or even, in some cases, substitutive source of evidence compared to the expensive evidence obtained from randomised controlled trials

Clinical update: The important role of dual kidney function testing (ACR and eGFR) in primary care: Identification of risk and management in type 2 diabetes

Diabetic kidney disease (DKD) is common complication of type 1 and type 2 diabetes and may lead to progressive kidney dysfunction culminating in end-stage kidney disease. Kidney function is evaluated less frequently than other care procedures in patients with diabetes, even though the opportunity to identify DKD early and slow or even halt renal damage early in the disease progression represents a potentially important clinical opportunity for early intervention. The following review provides an overview of the under-recognised importance of kidney function in T2D and current best-practice to support the identification of DKD as part of primary care T2D management

Racial, ethnic and regional differences in the effect of sodium–glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes: a systematic review and meta-analysis of cardiovascular outcome trials

Objectives The cardiorenal protective effects of sodium–glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Design Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. Participants people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs. Main outcome measures Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled. Results In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high. Conclusions There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation. PROSPERO Registration: CRD42023401734</p

Reply to Mantovani: "Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes"

We thank Mantovani for the interest and appreciation in our meta‐analysis. In a comment letter, three points were raised, all concerning the association between non‐alcoholic fatty liver disease (NAFLD) and risk of incident cardiovascular disease (CVD)

Prevention of Microvascular Complications of Diabetes

Global prevalence estimates from 2019 suggest that the number of people diagnosed with diabetes was 463 million and is projected to increase to 700 million by the year 2045.1 The growing prevalence and increase in life-years spent with diabetes has a significant impact on the development of macrovascular and microvascular complications and places a huge societal and financial burden on almost every health care system in the world.2 Although, declining trends in cardiovascular complications, cardiovascular-related mortality and lower extremity amputation rates have been reported over the last 2 decades, particularly from high-income countries including Europe and North America, the global burden of cardiovascular disease, blindness due to retinopathy, and end-stage kidney disease (ESKD) in people with diabetes compared with those without has increased alarmingly.3 The “DISCOVER” observational study program from 2014 to 2019 reported that the global crude prevalence of microvascular complications in people with type 2 diabetes was 18.8%, being highest in Europe (23.5%) and lowest in Africa (14.5%).4 Among individuals with a median duration of type 2 diabetes of 4.1 years, the prevalence of peripheral neuropathy was 7.7%, chronic kidney disease 5.0%, and albuminuria 4.3%. </p

Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: A meta-analysis with bias analysis

BACKGROUND & AIMS: A causal association of non-alcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and type 2 diabetes (T2DM) remains unproved. We aimed to quantify the likelihood of causality examining the sensitivity of observational associations to possible confounding. METHODS: Studies investigating longitudinal associations of NAFLD with CVD or T2DM were searched on 5 June 2018. Study-specific relative risks (RRs) were combined in random-effects meta-analyses and pooled estimates used in bias analyses. RESULTS: Associations of NAFLD with CVD and T2DM were reported in 13 (258 743/18 383 participants/events) and 20 (240 251/12 891) studies respectively. Comparing patients with NAFLD to those without, the pooled RR was 1.48 (95% CI: 0.96, 2.29) for CVD and 2.17 (1.77, 2.65) for T2DM. In bias analyses, for an unmeasured confounder associated to both NAFLD and CVD with a RR of 1.25, the proportion of studies with a true (causal) effect of NAFLD on CVD surpassing a RR of 1.10 (ie, 10% increased risk of CVD in participants with NAFLD) was 0.67 (95% CI: 0.42, 0.92) while for 75% increase, it was 0.36 (0.11, 0.62). Corresponding figures for T2DM were 0.97 (0.91, 1.00) for a 10% increased risk of T2DM in participants with NAFLD to 0.70 (0.49, 0.92) for a 75% increase. CONCLUSIONS: The results of this study are strongly suggestive for a causal relationship between NAFLD and T2DM, while the evidence for a causal link between NAFLD and CVD is less robust. Therapeutic strategies targeting NAFLD are likely to reduce the risk of developing T2DM

Deprescribing, Polypharmacy and Prescribing Cascades in Older People with Type 2 Diabetes: A Focused Review

Deprescribing is the process by which medications are reduced without compromising safety to the patient (Jude et al. in 2022 Diabetes Ther 13: 619–634, 2022). The purpose of this narrative review is to discuss deprescribing as a topic, firstly discussing the benefits and pitfalls to such pharmacological interventions along with the current barriers and enablers to such a controversial topic, and then discussing deprescribing with respect to preventive medications, namely those that reduce the long term impacts of a condition or disease. Research that has previously focused on reducing polypharmacy has highlighted the benefits of such interventions, including reduction of adverse reactions or complications, improved patient satisfaction and quality of life, and improved cost effectiveness and drug compliance. Some potential harms that have been highlighted include an increased number of complications, increased symptoms of previously dampened conditions, and negligible changes in patient satisfaction that have stressed the importance of this intervention being patient centred and individualized to each patient. The implementation of deprescribing processes could drastically change the way people think about deprescribing and could be extremely beneficial to older patients living with type 2 diabetes worldwide. Developments in preventive medication deprescribing could pave the way for this intervention to become more common place improving the quality of life in patient’s final years.</p

Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: Systematic analysis of cardiorenal outcome trials in type 2 diabetes

Aims: Most trials leading to the approval of glucagon-like peptide receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2is) were primarily designed to confirm their non-inferiority to placebo (commonly using an upper 95% confidence limit threshold of 1.3) and, if confirmed, superiority (threshold 1): this asymmetry of margins (1 vs. 1.3) favours the active intervention. We aimed to quantify the probability of clinical superiority of the active treatment by applying the same threshold used to claim non-inferiority. Materials and Methods: We searched PubMed and Cochrane CENTRAL for cardiorenal outcome trials in subjects with type 2 diabetes published before 5 December 2021, to reconstruct from Kaplan-Meier plots individual-level data for the primary outcome or all-cause mortality. We calculated Bayesian posterior densities to obtain the probability for a treatment effect (hazard ratio)   Results: We extracted data from 27 Kaplan-Meier plots (18 for the primary outcome, nine for mortality). Probabilities of clinical superiority to placebo varied significantly: for GLP-1RAs, from a minimum of 0% to a maximum of 69% for the primary outcome and from 0% to 8% for mortality; corresponding estimates for SGLT2is were 0% to 96% and 0% to 93%. Probabilities were on average greater for SGLT2is, particularly in trials investigating kidney or heart failure outcomes. Conclusions: The probability of clinical superiority to placebo varies widely across trials previously reported as showing superiority of GLP-1RAs or SGLT2is compared with placebo. These results showed within- and between-class differences, highlight the drawbacks of a binary interpretation of the results, particularly in the context of the current designs of non-inferiority trials, and have implications for decision makers and future clinical recommendations.</p

Patient and public involvement for ethnic minority research: an urgent need for improvement

Inequalities in health by ethnicity persist in the UK, and there is a history of health research failing to address the needs of ethnic minorities. The COVID-19 pandemic has further highlighted ethnic health disparities1 and emphasised the need for a greater ethnic minority contribution to all aspects of research. Ethnic minority patient and public involvement needs to go beyond just inclusion in research design, but to encompass active involvement in setting research questions, helping shape study design, being co-applicants, actively informing study implementation, data analysis and interpretation, and dissemination of findings.2,3 A prerequisite for this is the development of a wider patient and public involvement community which is reflective of our growing population diversity.</div